From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,misc.health.alternative
Subject: HIV Long Term Non-Progressors, Part I  (was Re: long-term HIV 
	"survival")
Date: Mon, 17 Aug 1998 06:12:37 GMT

WHAT'S DIFFERENT ABOUT LONG TERM NON-PROGRESSORS INFECTED WITH
HIV?

Steven B. Harris, M.D.

   One of the problems with talking about "long term
nonprogressors" (LTNPs) in HIV infection, is that there are
multiple definitions of the term.  Most require non-progression
for some years off all treatment, which makes the oft heard
statement that they all have lack of medical treatment in common,
a mere tautology.  By definition, they do.  The remarkable
observation that long term non progressors don't take antivirals
is often no more remarkable than the observation that mammals all
produce milk for their young.

  Again, people who don't progress for years, but are in treat-
ment, are not called long term non-progressors.  These people,
however, exist in large numbers.  In the Concorde study, for
example, with very large groups, the "late treatment" group of
HIV infected men were not given AZT until their lymphocyte count
had fallen below a certain level or they developed symptoms of
AIDS.  By three years, half of this group was still untreated,
meaning that 50% had progressed even without AZT.  In the AZT
group, a similar number of men had progressed, and 20% had died
of AIDS.  This leaves another 50% of men who had not progressed
by the criteria of the study, and surely many of them would have
been labeled "non progressors" had it not been for the fact that
they were taking AZT.

   Similarly, in the abstract below, 5 year survival is 54% for
patients taking AZT.  Surely there would be some long term non
progressors in this group, if it were not for the fact that they
all were talking AZT.


Rev Invest Clin 1994 Nov;46(6):491-493
Survival of patients with advanced HIV infection treated with 300
mg/d of zidovudine: a prospective study.

Ruiz-Arguelles GJ, Lagunes-Yannelli B, Mercado-Diaz L, Aleman-H-
oey DD

Centro de Hematologia y Medicina Interna de Puebla, Mexico.

In this prospective study we analyze the long-term survival using
300 mg/day zidovudine (AZT) in patients with advanced forms of
human immunodeficiency virus infection. The study is in a
private-practice setting, over a 5-year period, and includes 72
patients with advanced human immunodeficiency virus infection
(categories C1, 2 or 3). The median survival (SV) is above 60
months (24-months SV 65% and 60-month SV 54%). According to the
number of CD4 cells at diagnosis it was found that patients with
above or below 200 CD4 T cells had a median SV of above 60 and 18
months (p < 0.001) and a 24-month SV 88 and 45% (p < 0.001); for
patients with CD4 cells below 20 at diagnosis, the median
survival was even lower (three months) and the 12-month survival
less than 18%. It is concluded that the results of treating
HIV-infected patients with AZT 300 mg/day are similar to those
reported by others using higher doses of AZT. A low dosage is
also more easily available to a larger number of HIV-infected
individuals.
---------------------------------------------------------------


Comment:

     Finally, it needs to be pointed out that there is a very
large amount of evidence that it is not lack of antiviral use
which distinguishes long term non progressors (LTNPs) in HIV
infection.  These people have (occasionally) been found to be
infected with defective viruses (vpr, vpu and nef deletions), and
sometimes there is evidence that these mutations have been
selected for by the host's own defence systems.  However, these
are not the most common reasons for long term non progression.
Viruses from cells from LTNPs don't grow well in culture, often,
and viral loads in LTNPs in almost all papers are seen to be low
in plasma and in lymph cells.  Several host factor studies show
that LTNPs are much more likely to have much high proportions of
deletions in CCR5 and CCR2b, which are receptors on macrophages
which HIV uses to gain entry to these cells.  They also have
different anti-HIV antibody profiles, and different CD8 and CD4
balances in antiviral response.  An article by Levy (below) makes
these points, and should be read by anybody under the impression
that Levy thinks that LTNP is due to avoidance of antiviral
treatment (except in the definitional sense of LTNP).


Hosp Pract (Off Ed) 1994 Oct 15;29(10):41-44
Long-term survivors of HIV infection.

Levy JA

Department of Medicine, University of California, San Francisco,
School of Medicine.

The persistent immune competence seen in a small percentage of
HIV-infected individuals reflects the heterogeneity of both the
virus and the host. Some HIV strains, for example, are more
cytopathic than others. Host factors that promote longer survival
lack "enhancing" antibodies, an appropriate balance of
two crucial CD4+ cell subsets and their cytokines, and a strong
CD8+ cell antiviral response.

Differential exposure to recreational drugs and other sexually
transmitted diseases does not explain ANY lack of progression to
AIDS in LTNP, even though skeptics claim these things are the
entire cause of AIDS before 1987.  This view would seem to be
impossible in light of the facts.  If illegal drugs were the
entire cause of AIDS before 1987, it would be rather difficult to
find that long term nonprogressors in 1994 had the same illegal
drug use as progressors, when this was documented by quest-
ionnaire in 1983.  Yet that is exactly what the study below
finds.


AIDS 1994 Aug;8(8):1123-1128
Long-term HIV-1 infection without immunologic progression.

Buchbinder SP, Katz MH, Hessol NA, O'Malley PM, Holmberg SD

AIDS Office, Department of Public Health, San Francisco, Califor-
nia 94102.

OBJECTIVE: To identify and describe a subgroup of men infected
with HIV for 10-15 years without immunologic progression, and to
evaluate the effect of sexually transmitted diseases (STD) and
recreational drug use on delayed HIV disease progression. DESIGN:
Inception cohort study. SETTING: Municipal STD clinic. PARTICI-
PANTS: A total of 588 men with well documented dates of HIV
seroconversion and 197 HIV-seronegative controls. MAIN OUTCOME
MEASURES: AIDS, CD4+ count, rate of CD4+ cell loss, CD8+ count,
beta 2-microglobulin, complete blood count, p24 antigen and
HIV-related symptoms. RESULTS: Of 588 men, 69% had developed AIDS
by 14 years after HIV seroconversion (95% confidence interval,
64-73%). Of 539 men with HIV seroconversion dates prior to 1983,
42 men (8%) were healthy long-term HIV-positives (HLP), HIV-inf-
ected > or = 10 years without AIDS and with CD4+ counts > 500 x
10(6)/l. When compared with progressors (men with HIV seroconv-
ersion prior to 1983 but with AIDS or CD4+ counts < 200 x 10(6)/-
l), HLP had a significantly slower rate of CD4+ decline (6
versus 85 x 10(6)/l cells/year), and less abnormal immunologic,
hematologic and clinical parameters. However, when compared with
HIV-uninfected controls, HLP demonstrated lower CD4+ counts and
mild hematologic abnormalities. There were no consistent diffe-
rences between HLP and progressors in prior exposure to recrea-
tional drugs or STD. CONCLUSION: There are individuals with
long-term HIV infection who appear clinically and immunologically
healthy 10-15 years after HIV seroconversion, with stable CD4+
counts. Lack of exposure to STD or recreational drugs does not
appear to explain the delayed course of disease
progression in HLP.

Comments:
  Comment in: AIDS 1994 Aug;8(8):1179-82




---------

J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jul 1;18(3):
229-233   HIV-1-infected long-term slow progressors heterozygous
for delta32-CCR5 show significantly lower plasma viral load than
wild-type slow progressors.

Walli R, Reinhart B, Luckow B, Lederer E, Loch O, Malo A, Wank R,
Schlondorff D, Goebel FD

Medizinische Poliklinik, Klinikum Innenstadt, Ludwig-Maximilians-
-Universitat Munchen, Germany.
[Medline record in process]

OBJECTIVE: Patients heterozygous for delta32-CCR5 may have a
delayed progression of HIV-1 disease. The aim of the present
study was to investigate the influence of CCR5/delta32-CCR5
genotype in long-term slow progressors using plasma viral load as
a marker of disease progression. DESIGN: We analyzed 70
long-term slow progressors (diagnosis > 8 years previously; CD4
count > 500/microl; asymptomatic, never received antiretroviral
therapy) for CCR5 genotype, plasma viral load, and lymphocyte
subsets. Distribution of CCR5 genotypes was compared with a
cohort of 61 multiply exposed noninfected individuals and a group
of 336 control subjects. All study participants were white.
METHODS: CCR5 genotype was determined by polymerase chain
reaction (PCR) amplification. Plasma viral load was quantified by
branch DNA hybridization, lymphocyte subsets were determined by
fluoresence-activated cell sorter (FACS) analysis. The Mann-Whi-
tney-Wilcoxon test was used for statistical analyses. RESULTS:
The frequency of the CCR5/delta32-CCR5 heterozygote genotype was
higher in long-term slow progressors (37.1%) and multiply exposed
noninfected individuals (26.2%), compared with the control group
(15.8%). In addition, plasma viral load was found to be signifi-
cantly lower in CCR5/delta32-CCR5 heterozygous long-term slow
progressors (median < log10 2.70; 53.8% < log10 2.70; 0% > log10
4.0) relative to that seen in CCR5/CCR5 long-term slow
progressors (median log10 3.64; 22.7% < log10 2.70; 22.7% > log10
4.0). CONCLUSIONS: These findings strengthen the hypothesis of a
favorable influence of CCR5/delta32-CCR5 genotype on progression
of HIV-1 infection. Therefore, evaluation of CCR5 genotype might
influence antiretroviral therapy strategies in early stages of
HIV-1 infection.

J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jun 1;18(2):110--
116
Chemokine receptor CCR2b 64I polymorphism and its relation to CD4
T-cell counts and disease progression in a Danish cohort of
HIV-infected individuals. Copenhagen AIDS cohort.

Eugen-Olsen J, Iversen AK, Benfield TL, Koppelhus U, Garred P
Department of Infectious Diseases, Copenhagen University Hospita-
ls, Hvidovre, Denmark. jeo@biobase.dk

We have investigated the role of the recently described mutation
in CCR2b named 64I in relation to HIV resistance, CD4 T-cell
counts, and disease progression in Danish individuals by polymer-
ase chain reaction (PCR)-based methods as well as sequenced
full-length CXCR4 and CCR5 genes from HIV-infected long-term
nonprogressors for possible mutations. In total, 215 Danish
individuals were analyzed for 64I allele frequency; disease
progression was followed in 105 HIV-1-positive homosexual Danish
men from their first known positive HIV-1 test result and up to
11 years. In 87 individuals, the CD4 T-cell count was monitored
closely. We found no significant difference in 64I allele
frequency between HIV-1-seropositive persons (0.08), high-risk
HIV-1-seronegative persons (0.11), and blood donors (0.06). No
significant difference was observed in annual CD4 T-cell decline,
CD4 T-cell counts at the time of AIDS, in AIDS-free survival as
well as survival with AIDS, between 64I allele carriers and
wild-type individuals. Among 9 long-term nonprogressors, 2
carried the 64I allele, while none of 9 fast progressors carried
the 64I allele. However, this was not significantly different
(p=.47). Long-term nonprogression could not be explained by CXCR4
polymorphism or other polymorphisms in the CCR5 gene than
the CCR5delta32 allele. Furthermore, we were not able to detect
any significant independent effect of the 64I allele on developm-
ent to AIDS, overall survival, and annual CD4 T-cell decline in
this cohort.

Ann Intern Med 1997 Nov 15;127(10):882-890
Association between CCR5 genotype and the clinical course of
HIV-1 infection.

de Roda Husman AM, Koot M, Cornelissen M, Keet IP, Brouwer M,
Broersen SM, Bakker M, Roos MT, Prins M, de Wolf F, Coutinho RA,
Miedema F, Goudsmit J, Schuitemaker H

Central Laboratory of the Red Cross Blood Transfusion Service,
University of Amsterdam Academic Medical Center, The Netherlands.

BACKGROUND: Heterozygosity for a 32-nucleotide deletion in the
C-C chemokine receptor 5 gene (CCR5 delta 32) is associated with
delayed disease progression in persons infected with HIV-1.
OBJECTIVE: To compare the predictive value of CCR5 genotype with
that of established markers in the clinical course of HIV-1
infection. DESIGN: Retrospective longitudinal study and nested
case-control study. The latter included only long-term survivors,
who were individually matched with progressors. SETTING: Amsterd-
am, the Netherlands. PARTICIPANTS: 364 homosexual men with HIV-1
infection. MEASUREMENTS: Polymerase chain reaction was used for
CCR5 genotyping. Univariate and multivariate Cox proportional
hazard analyses were done for disease progression with CCR5
genotype, CD4+ T-lymphocyte counts, T-lymphocyte function, HIV-1
biological phenotype (syncytium-inducing or non-syncytium-induci-
ng HIV-1), and viral RNA load in serum as covariates. RESULTS: In
the case-control study, 48% of long-term survivors were hetero-
zygous for CCR5 delta 32 compared with 9% of progressors (odds
ratio, 6.9 [95% CI, 1.9 to 24.8]). In the total study sample,
CCR5 delta 32 heterozygotes had significantly delayed disease
progression (P < 0.001; relative hazard, 0.4 [CI, 0.3 to 0.6]), a
1.5-fold slower decrease in CD4+ T-lymphocyte count (P = 0.01),
and a 2.6-fold lower viral RNA load (P = 0.01) at approximately
2.3 years after seroconversion compared with CCR5 wild-type
homozygotes. At the end of the study, both groups showed the same
prevalence of syncytium-inducing HIV-1, but CCR5 delta 32
heterozygotes had a delayed conversion rate. The protective
effect of CCR5 delta 32 heterozygosity was stronger in the
presence of only non-syncytium-inducing HIV-1. The CCR5 genotype
predicted disease progression independent of viral RNA load, CD4+
T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological
phenotype. CONCLUSIONS: The addition of CCR5 genotype to current-
ly available laboratory markers may allow better estimation of
the clinical course of HIV-1 infection.


J Acquir Immune Defic Syndr Hum Retrovirol 1997 Sep 1;16(1):10-14

HIV-infected individuals with the CCR delta32/CCR5 genotype have
lower HIV RNA levels and higher CD4 cell counts in the early
years of the infection than do patients with the wild type.
Copenhagen AIDS Cohort Study Group. Katzenstein TL, Eugen-Olsen
J, Hofmann B, Benfield T, Pedersen C, Iversen AK, Sorensen AM,
Garred P, Koppelhus U, Svejgaard A, Gerstoft J

Department of Infectious Diseases, Rigshospitalet, Copenhagen,
Denmark.

The relations among serum HIV RNA levels, CD4 cell counts,
presence of the mutant CCR5-allele in heterozygous form, and
clinical outcome was analyzed in 96 patients from the Copenhagen
AIDS Cohort. In the early years of the infection, patients with
the CCR5 delta32/CCR5 genotype had significantly lower HIV RNA
levels (p = 0.005) and higher CD4 cell counts (p < 0.005) than
did patients homozygous for the normal allele. The long-term
clinical benefit of being heterozygous is small and cannot solely
explain the large interpatient variation in progression rates.
The beneficial effect of being heterozygous seems to be mediated
by events in the early stages of the HIV infection.

Science 1997 Aug 15;277(5328):959-965
Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1
infection and disease progression. Hemophilia Growth and Develo-
pment Study (HGDS), Multicenter AIDS Cohort Study (MACS),
Multicenter Hemophilia Cohort Study (MHCS), San Francisco City
Cohort (SFCC), ALIVE Study.

Smith MW, Dean M, Carrington M, Winkler C, Huttley GA, Lomb DA,
Goedert JJ, O'Brien TR, Jacobson LP, Kaslow R, Buchbinder S,
Vittinghoff E, Vlahov D, Hoots K, Hilgartner MW, O'Brien SJ

Science Applications International Corp. Frederick, National
Cancer Institute, Frederick, MD 21702-1201, USA.

The critical role of chemokine receptors (CCR5 and CXCR4) in
human immunodeficiency virus-type 1 (HIV-1) infection and
pathogenesis prompted a search for polymorphisms in other chemok-
ine receptor genes that mediate HIV-1 disease progression. A
mutation (CCR2-64I) within the first transmembrane region of the
CCR2 chemokine and HIV-1 receptor gene is described that occurred
at an allele frequency of 10 to 15 percent among Caucasians and
African Americans. Genetic association analysis of five acquired
immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed
that although CCR2-64I exerts no influence on the incidence of
HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I
allele progressed to AIDS 2 to 4 years later than individuals
homozygous for the common allele. Because CCR2-64I occurs invari-
ably on a CCR5-+-bearing chromosomal haplotype, the independent
effects of CCR5-Delta32 (which also delays AIDS onset) and
CCR2-64I were determined. An estimated 38 to 45 percent of AIDS
patients whose disease progresses rapidly (less than 3 years
until onset of AIDS symptoms after HIV-1 exposure) can be
attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the
survival of 28 to 29 percent of long-term survivors, who avoid
AIDS for 16 years or more, can be explained by a mutant genotype
for CCR2 or CCR5.


J Virol 1998 Jul;72(7):6215-6217
CXCR4 and CCR5 genetic polymorphisms in long-term nonprogressive
human immunodeficiency virus infection: lack of association with
mutations other than CCR5-Delta32.

Cohen OJ, Paolucci S, Bende SM, Daucher M, Moriuchi H, Moriuchi
M, Cicala C, Davey RT Jr, Baird B, Fauci AS

Laboratory of Immunoregulation, National Institute of Allergy and
Infectious Diseases, Bethesda, Maryland 20892-1876, USA.
OCohen@nih.gov

Polymorphisms in the coding sequences of CCR5 and CXCR4 were
studied in a group of human immunodeficiency virus (HIV)-infected
long-term nonprogressors. Two different point mutations were
found in the CXCR4 coding sequence. One of these CXCR4 mutations
was silent, and each was unique to two nonprogressors. The
well-described 32-bp deletion within the CCR5 coding sequence
(CCR5-Delta32) was found in 4 of 13 nonprogressors, and 12
different point mutations were found scattered over the CCR5
coding sequence from 8 nonprogressors. Most of the mutations
created either silent or conservative changes in the predicted
amino acid sequence: only one of these mutations was found in
more than a single nonprogressor. All nonsilent mutations were
tested in an HIV envelope-dependent fusion assay, and all
functioned comparably to wild-type controls. Polymorphisms in the
CXCR4 and CCR5 coding sequences other than CCR5-Delta32 do not
appear to play a dominant mechanistic role in nonprogression
among HIV-infected individuals.

[Note: this paper did not look at CCR2b]

Continued in next message



.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: misc.health.aids,sci.med,misc.health.alternative
Subject: HIV Long Term Nonprogressors, Part II (was: Re: long-term HIV 
	"survival")
Date: Mon, 17 Aug 1998 06:12:40 GMT

What's different about long term non-progressors (LTNPs), continued:
Part II

Steven B. Harris, M.D.


Here are some other differences in LTNPs and their viruses:


J Virol 1995 Sep;69(9):5838-5842
High levels of anti-human immunodeficiency virus type 1 (HIV-1)
memory cytotoxic T-lymphocyte activity and low viral load are
associated with lack of disease in HIV-1-infected long-term
nonprogressors.

Rinaldo C, Huang XL, Fan ZF, Ding M, Beltz L, Logar A, Panicali
D, Mazzara G, Liebmann J, Cottrill M, et al

Department of Pathology, University of Pittsburgh School of
Medicine, Pennsylvania, USA.

Lack of disease in long-term nonprogressors with human immunodef-
iciency virus type 1 (HIV-1) infection was strongly associated
with very low copy numbers of HIV-1 DNA and RNA in peripheral
blood mononuclear cells and plasma and the presence of high
levels of anti-HIV-1 CD8+ memory cytotoxic T lymphocytes
specific for Gag, Pol, and Env, compared with levels present in
intermediate and advanced progressors. CD8+ memory cytotoxic T
lymphocytes may have an important role in controlling HIV-1
replication and preventing disease in long-term nonprogressors.


AIDS 1998 Jun 18;12(9):985-997
Rare mutations in a domain crucial for V3-loop structure prevail
in replicating HIV from long-term non-progressors.

Menzo S, Sampaolesi R, Vicenzi E, Santagostino E, Liuzzi G,
Chirianni A, Piazza M, Cohen OJ, Bagnarelli P, Clementi M

Istituto di Microbiologia, Universita di Ancona, Italy.


[Medline record in process]

OBJECTIVE: To evaluate the role of the selective forces exerted
by the host on the HIV-1 structures involved in viral entry.
DESIGN AND METHODS: The V3 region of the env gene was analysed in
cell-free HIV-1 RNA from 17 infected subjects: 11 long-term
non-progressors (LTNP) and six symptomless, typical progressor
patients. To evaluate the potential biological significance of
one of the rare variants detected in the LTNP, it was reproduced
by recombinant PCR into a HIV-1 molecular clone. RESULTS: The
intrapatient divergence of the V3-loop sequences averaged 8.62%
in LTNP and 5.29% in progressors, although LTNP displayed lower
divergence from the clade B consensus than progressors (16.65
and 19.76%, respectively). The analysis of non-synonymous and
synonymous substitutions indicated that selective pressure was
exerted in this region in both LTNP and progressors. Individual
peculiarities (unique and rare V3-loop variants) emerged,
however, in most sequences from LTNP, and variants bearing
mutations in a domain crucial for the V3-loop structure were more
prevalent in LTNP (P = 0.0012). The pNL4-3-derived mutant
reproducing a V3-loop variant detected in a LTNP was efficiently
expressed upon transfection, but the mutant virus was nearly
completely unable to infect CD4+ cell lines, activated primary
peripheral blood lymphocytes, or monocyte-derived macrophages,
suggesting that a defect impaired the entry phase of the replica-
tion cycle. CONCLUSIONS: The results indicate that host factors
impose selective constraints on the evolution of the HIV-1
structures involved in viral entry. In LTNP, these factors are
likely to force the virus into attenuated variants.


NB:  The papers below represent many papers exploring how
difficult it is to define long term non-progression.  Even people
with stable immune systems for many years of HIV infection, can
suddenly develop a strain of virus which
begins to cause immune destruction.


----------

J Acquir Immune Defic Syndr Hum Retrovirol 1998 Jun 1;18(2):155--
161
Longitudinal HIV-1 RNA levels in a cohort of homosexual men.

O'Brien TR, Rosenberg PS, Yellin F, Goedert JJ

Viral Epidemiology Branch, National Cancer Institute, Public
Health Service, U.S. Department of Health and Human Services,
Rockville, Maryland 20852, USA.

HIV-1 RNA levels measured during early chronic infection strongly
predict subsequent clinical events. In the short term, HIV-1 is
in a steady state, but the stability of viral levels over time is
incompletely understood. We used reverse transcriptase polymerase
chain reaction (RT-PCR) to examine changes in serum HIV-1 RNA
levels in 111 HIV-1-infected homosexual men during the period
from 1982 to 1992 and their relation to clinical outcomes. HIV-1
RNA levels increased by a median of 0.08 log10 copies/ml/year
(p=.0001). HIV-1 RNA levels rose either gradually or abruptly for
the majority of subjects; 41% had no increase. Among subjects
surviving at least 8 years, HIV-1 RNA was stable during the first
4 years after seroconversion (median. 0.00 log10 copies/ml/year),
but rose in years five through eight (median, 0.06 log10 copie-
s/ml/year; p=.04). The annual HIV-I RNA level was more predictive
of AIDS (relative hazard [RH], 1.75 per 0.5 log difference; 95%
confidence interval [CI], 1.38-2.21; likelihood ratio [LR], 26.2)
than the initial level alone (RH,1.39; 95% CI. 1.10-1.76; LR,
8.5). We conclude that most HIV-1-infected persons lack a
long-term viral setpoint and that failure to account for evolut-
ion of the viral level can lead to underestimation of the risk of
progression.

Blood 1997 Aug 1;90(3):1133-1140
Even individuals considered as long-term nonprogressors show
biological signs of progression after 10 years of human
immunodeficiency virus infection.

Lefrere JJ, Morand-Joubert L, Mariotti M, Bludau H, Burghoffer B,
Petit JC, Roudot-Thoraval F

Institut National de la Transfusion Sanguine, Paris, France.

Despite a decade of human immunodeficiency virus (HIV)
seropositivity, a few individuals termed as long-term nonprogr-
essors (LTNPs) maintain a stable CD4+ T-cell count for a period
of time. The aim of this study was to establish, through the
sequential determination of all known predictors of HIV disease,
the proportion of such patients having stringent criteria of true
long-term nonprogression. Among 249 individuals who were HIV-i-
nfected and prospectively followed up over a 10-year period (1985
to 1995), 12 having a CD4+ T-cell count greater than 500/microL
(LTNP I group) and 9 having a CD4+ T-cell count less than 500 but
stable over time (LTNP II group) after at least 10 years of
infection without intervention of antiviral therapy, were studied
over the entire follow-up period. The plasma HIV RNA copy number
and the serum concentrations of p24 antigen, each anti-HIV
antibody, neopterin, beta-2-microglobulin, Immunoglobulin (Ig) G
and IgA were determined every 18 months over the study period.
Cellular and plasma viremias were cross-sectionaly assayed in all
21 patients. Only two patients had strictly no marker of
progression over the follow-up period. They were the only ones
who had, over the 10-year period, a viral copy number too low to
be detected. The other patients had a viral copy number higher
than 400/mL at at least one visit and increasing over the follow-
-up period, and they evidenced one or more markers of virological
or immunological deterioration. Cellular viremia was positive in
all patients but two, while plasma viremia was negative in all
but one. The population of individuals termed as LTNPs is not
virologically and immunologically homogeneous. The majority
present biological signs of HIV disease progression. A new
pattern of true LTNP can be drawn through stringent
criteria based on the whole known predictors. This pattern
appears to be rare in HIV-positive population.

J Acquir Immune Defic Syndr Hum Retrovirol 1997 Mar 1;14(3):243--
248
How many HIV-infected individuals may be defined as long-term
nonprogressors? A report from the Italian Seroconversion Study.
Italian Seroconversion Study Group.

Petrucci A, Dorrucci M, Alliegro MB, Pezzotti P, Rezza G, Sinicco
A, Lazzarin A, Angarano G

Centro Operativo AIDS, Laboratorio di Epidemiologia e Biostatist-
ica-Instituto Superiore di Sanita, Rome, Italy..

We prospectively examined a cohort of HIV-positive persons with
an accurately estimated date of HIV seroconversion who were
infected through injecting drug use or sexual contact to estimate
the proportion of long-term nonprogressors (LTNP), considering
four definitions of LTNPs. We also evaluated whether factors such
as gender, age, and HIV-exposure category were associated with
being LTNP; we determined the overlap among the definitions and
compared the CD4 and CD8 counts and the CD4/CD8 decline among
LTNPs and "moderate" and "fast" progressors. Of the 528 persons
selected for analysis, 2 to 4% were considered LTNPs, depending
on the definition. The proportion of LTNPs varied by definition,
and there was little overlap among definitions. The LTNPs did
not appear to differ from "moderate" and "fast" progressors with
regard to main demographic characteristics, and they showed a
better trend of immunological parameters, appearing to have a
slower progression rather than a permanently arrested infection.

Comments: Comment in: J Acquir Immune Defic Syndr Hum Retrovirol
1997 Dec 15;16(5):409-11

-------------------------------------------------------
Nef gene dysfunction:


Below is the famous Learmont cohort of transfusion recipients,
who all got a strain of HIV with a nef deletion.  All have done
well, with the  exception of one person given steroids for Lupus.
Nef damaged SIV mutants do not cause AIDS in monkeys, although
back-mutation to the wild type is ever a danger unless the nef
gene has been deleted entirely.


AIDS 1997 Nov;11(13):1565-1574
Lymphoproliferative immune function in the Sydney Blood Bank
Cohort, infected with natural nef/long terminal repeat mutants,
and in other long-term survivors of transfusion-acquired HIV-1
infection.

Dyer WB, Geczy AF, Kent SJ, McIntyre LB, Blasdall SA, Learmont
JC, Sullivan JS

New South Wales Red Cross Blood Transfusion Service, Sydney,
Australia.

OBJECTIVES: To assess T-helper cell immune function (proliferati-
on) in members of the Sydney Blood Bank Cohort (SBBC) compared
with other individuals with transfusion- and sexually acquired
HIV-1 infection and with matched HIV-negative controls. DESIGN
AND METHODS: Decreasing CD4 counts and T-helper cell function are
associated with disease progression. Peripheral blood
mononuclear cells (PBMC) from study subjects were assayed for in
vitro proliferative responses to HIV-1-derived antigens, recall
antigens and alloantigen. T-helper cell function and CD4 counts
in members of the SBBC were followed longitudinally. RESULTS:
Proliferative responses and CD4 counts from members of the SBBC
were similar to or better than those of other transfusion-
or sexually-acquired HIV-1-positive long-term non-progressors
(LTNP), including the HIV-negative matched SBBC control groups.
However, individuals with disease progression had reduced or
undetectable proliferative responses to recall antigens but a
conserved response to alloantigen; they also had low CD4 counts
and low CD4:CD8 ratios. In the SBBC, these immune parameters were
usually stable over time. CONCLUSIONS: The unique SBBC with
natural nef/long terminal repeat deletions in the HIV-1 genome
were genuine LTNP without showing signs of disease progression.
They appeared to be a group distinct from the tail-end of
the normal distribution of disease progression rates, and may
remain asymptomatic indefinitely. The SBBC virus may form the
basis of a live attenuated immunotherapeutic or immunoprophy-
lactic HIV vaccine.


Note that nef dysfunction is apparently NOT a common cause of
long term survival with HIV, however.


J Virol 1995 Dec;69(12):8142-8146
Biological characterization of nef in long-term survivors of
human immunodeficiency virus type 1 infection.

Huang Y, Zhang L, Ho DD

Aaron Diamond AIDS Research Center, New York University School of
Medicine, New York 10016, USA.

We have previously shown that there were no gross deletions or
obvious sequence abnormalities within nef of human immunodeficie-
ncy virus type 1 (HIV-1) in the 10 long-term survivors studied
(Y. Huang, L. Zhang, and D. D. Ho, J. Virol. 69:93-100, 1995).
Here we extend our study to examine these nef alleles in a
functional context. Using a new technique, termed site-directed
gene replacement, we have precisely replaced the nef of an
infectious molecular clone, HIV-1HXB2, with nef alleles derived
from 10 long-term survivors as well as from a patient with AIDS.
The replication properties of these chimeric viruses demonstrated
that the nef alleles derived from long-term survivors
neither significantly increased nor decreased viral replication,
compared with the nef allele of Nef+ HIV-1HXB2 and that derived
from a patient with AIDS. However, Nef+ viruses always replicated
faster than virus lacking nef. Moreover, single-cell infection
analysis by the MAGI assay showed that these chimeric viruses, as
well as Nef+ HIV-1HXB2, were more infectious than Nef-
HIV-1HXB2 was. Therefore, we conclude that the genotypic and
phenotypic features of nef are not likely to account for the
nonprogression of HIV-1 infection in the 10 cases studied, unless
the function of the nef gene in vivo
is not accurately reflected by the in vitro assays we used.


Serum HIV viral load is a strong predictor of progression to AIDS
in  hemophiliacs.  This certainly does not credence to the idea
that AIDS in hemophiliacs is due to factor toxicity.


JAMA 1996 Jul 10;276(2):105-110
Serum HIV-1 RNA levels and time to development of AIDS in the
Multicenter Hemophilia Cohort Study.

O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen
AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ,
Kroner BL, Goedert JJ

Viral Epidemiology Branch, National Cancer Institute, Rockville,
MD 20852, USA.

OBJECTIVE--To determine if the long-term incidence of the
acquired immunodeficiency syndrome (AIDS) is related to human
immunodeficiency virus type 1 (HIV-1) RNA levels measured early
in HIV-1 infection. DESIGN--Epidemiologic cohort study. SETTIN-
G--Five hemophilia treatment centers in the United States.
SUBJECTS--A total of 165 subjects with hemophilia and
HIV-1 infection (age at HIV-1 seroconversion, 1-66 years)
followed from 1979 to 1995. METHODS--The HIV-1 RNA level was
measured by polymerase chain reaction over a range of 200 to 1
million or more HIV-1 RNA copies/mL in archived serum
specimens collected 12 to 36 months (median, 27 months) after the
estimated date of HIV-1 seroconversion. Kaplan-Meier methods were
used to examine the risk of AIDS and proportional hazards models
were used to estimate relative hazards. RESULTS--The HIV-1 RNA
values were similar in subjects younger than 17 years at seroc-
onversion (median, 5214 copies/mL) and those 18 to 34 years old
(median, 4693 copies/mL), but higher in those 35 years or older
(median, 12069 copies/mL) (P = .02 compared with each younger
group). At 10 years after seroconversion, the proportions of
subjects with AIDS were 72% among subjects with 100,000 or more
HIV-1 RNA copies/mL measured 12 to 36 months after HIV-1
seroconversion (n = 9), 52% among subjects with 10,000 to 99,999
copies/mL (n = 55), 22% among subjects with 1000 to 9,999 copies-
/mL (n = 82), and 0% among subjects with fewer than 1000 copies-
/mL (n = 19) (P < .001). The age-adjusted relative hazard for
AIDS for subjects with 10,000 or more copies/mL was 14.3
(95% confidence interval, 1.9-105.6) compared with subjects with
fewer than 1000 copies/mL. CONCLUSIONS--The HIV-1 RNA level
during early chronic HIV-1 infection is a strong, age-independent
predictor of clinical outcome; low levels define persons with a
high probability of long-term AIDS-free survival.

Comments:
  Comment in: JAMA 1997 Jan 1;277(1):20-1



Immunol Lett 1996 Jun;51(1-2):69-73
Correlates of protection in HIV infection and the progression of
HIV infection to AIDS.

Clerici M, Shearer GM

Cattedra di Immunologia, Universita degli Studi di Milano, Italy.
mago@imiucca.csi.unimi.it

Exposure to human immunodeficency virus (HIV) can result in HIV
infection which is defined by seroconversion and the detection of
HIV-specific antibodies. Nevertheless, in every cohort at risk
for HIV infection, individuals are present in whom seroconversion
is not observed despite multiple documented exposures to HIV.
Recent studies have shown that HIV-specific T-lymphocytes are
present in the peripheral blood of these HIV-exposed seronegative
individuals, suggesting that cell-mediated immunity (CMI) could
have a protective role in the prevention of HIV infection. In
most individuals who seroconvert, HIV infection is followed by a
long period of clinically asymptomatic latency which
ultimately results in the development of acquired immunodeficency
syndrome (AIDS). Although this progression is observed in the
majority of HIV-infected individuals, individuals exist who are
asymptomatic and have relatively high CD4 counts despite long--
lasting HIV infection. Analogous to that observed in seronegative
HIV-exposed individuals, strong HIV-specific CMI seems to be
characteristic of these HIV-seropositive (HIV+) long-term
non-progressors (LTNP). Because strong HIV-specific CMI is
present in HIV-seronegative individuals exposed to HIV and in
HIV+ LTNP, we believe that HIV-specific CMI may be the main
correlate of protection against HIV infection and against the
progression of HIV infection to AIDS.



----------
Immunol Lett 1996 Jun;51(1-2):7-13
Characterization of long-term survivors of human immunodeficiency
virus type 1 infection.

Cao Y, Qin L, Zhang L, Safrit J, Ho DD

Aaron Diamond AIDS Research Center, New York University School of
Medicine, NY 10016, USA.

A small population of HIV-1-infected individuals remains clinica-
lly healthy and immunologically normal for more than ten years.
We have studied ten subjects who have been asymptomatic with
normal and stable CD4+ lymphocyte counts, despite 12 to 16 years
of HIV-1 infection, to gain information on the determinants of
nonprogression. Multiple methods were used to determine the
viral load in their blood. Plasma cultures were uniformly
negative for infectious virus. However, particle-associated HIV-1
RNA was detectable in four subjects using a sensitive branched
DNA amplification assay. In peripheral blood mononuclear cells
(PBMC), infectious HIV-1 was quantified in three subjects using a
standard limiting-dilution culture method. Infectious virus
was recovered from another subject using a CD8-depleted culture.
In contrast, six subjects had no detectable infectious virus in
PBMC. All had detectable viral DNA in PBMC by a quantitative
polymerase chain reaction assay, but the copy numbers were low,
ranging from 10 to 100 copies per 10(6) PBMC in all but two
subjects. Overall, the viral burden in the plasma and PBMC of
long-term survivors was orders of magnitude lower than those
typically found in progressors. Possible mechanisms for low
levels of HIV-1 in vivo were examined experimentally.


Immunol Lett 1996 Jun;51(1-2):3-6
Predominance of defective proviral sequences in an HIV +
long-term non-progressor.

Schwartz DH, Viscidi R, Laeyendecker O, Song H, Ray SC, Michael N

Department of Molecular Microbiology and Immunology, Johns
Hopkins School of Hygiene and Public Health, Baltimore, MD 21205,
USA.

We examined the accessory genes and envelope V3 region of
provirus obtained over a 5 year period from an HIV+ long-term
non-progressor with very low viral load and no in vitro recover-
able virus during that same time span. LTR sequences supported
normal Tat-mediated promoter activity. Multiple clones of
nef sequences were highly conserved with < 10% containing frame
shift or stop codon mutations. Functional analysis of the
predominant nef sequence indicated wild type downregulation of
surface CD4 and good function in a complementation infectivity
assay. By contrast, inactivating mutations were found in 64% of
amplicons containing vif, vpr, vpu, tat1, and rev1, and in 41% of
amplicons containing env V3. Identical inactive sequences were
obtained at an interval of 2 years, suggesting persistence of
quiescent defective provirus in a long-lived clonal cell popul-
ation. Furthermore, genetic distance versus time analysis
revealed an absence of progressive evolution or arborization of
quasispecies over time. This contrasts with data generated from
other asymptomatic HIV+ individuals. The non-progressive pattern
of env sequence diversity and low R2 for genetic divergence over
time suggests that the defective provirus circulating in the
periphery of this patient represents a randomly sampled "fossil
record" of earlier replication competent HIV-1 genomes.


Finally, here is an interesting paper showing that viral load
predicts even progression in cats with FIV.  So this immune
failure seen with lentiviruses is not a popper or AZT or
hemophilia factor thing.  It's something caused by high titers of
retrovirus.


J Virol 1996 Apr;70(4):2503-2507
Plasma viral RNA load predicts disease progression in accelerated
feline
immunodeficiency virus infection.

Diehl LJ, Mathiason-Dubard CK, O'Neil LL, Hoover EA

Department of Pathology, Colorado State University, Fort Collins,
Colorado
80523-1671, USA.

Viral RNA load has been shown to indicate disease stage and
predict the rapidity of disease progression in human immunodefic-
iency virus type 1 (HIV-1)-infected individuals. We had previou-
sly demonstrated that feline immunodeficiency virus (FIV) RNA
levels in plasma correlate with disease stage in infected cats.
Here we expand upon those observations by demonstrating that
plasma virus load is 1 to 2 logs higher in cats with rapidly
progressive FIV disease than in long-term survivors. Differences
in plasma FIV RNA levels are evident by 1 to 2 weeks after
infection and are consistent throughout infection. We also
evaluated humoral immune responses in FIV-infected cats for
correlation with survival times. Total anti-FIV antibody titers
did not differ between cats with rapidly progressive FIV disease
and long-term survivors. These findings indicate that virus
replication plays an important role in FIV disease progression,
as it does in HIV-1 disease progression. The parallels in
virus loads and disease progressions between HIV-1 and FIV
support the idea that the accelerated disease model is well
suited for the study of therapeutic agents directed at reducing
lentiviral replication.


.