A number of genetic and immunological factors have been
linked to an individual’s ability to control HIV replication after acquiring
infection. The contribution of properties of the virus has been less clear,
although certain subtypes of HIV have been associated with faster disease
progression (specifically subtype D). Two recent studies have attempted to shed
light on this issue by studying viral load levels among couples where there was strong evidence that one partner transmitted HIV to the other. One study was conducted in
heterosexual couples in Rakai, Uganda, while the other involved gay men in San
Francisco, USA. In both studies,
there was a statistically significant association between the viral load level
in the person who transmitted and the set point viral load level in the partner
who acquired the infection.
The researchers conclude that there are likely intrinsic
viral factors that contribute to the viral load level; in the larger of the two
studies it is estimated that these factors contribute approximately 16-37% of
the variance in viral load between different individuals. Both papers note that
an alternative explanation of the findings might be that viral load is linked
to the relative dose of virus that an individual is exposed to (which would
likely be higher if the transmitting partner has a high viral load); however, studies in the SIV model have not found evidence of a significant link between
the dose of virus animals are challenged with and the set point viral load.
Although the findings of these two independent studies are compelling, it must also be borne in mind that chronically infected
individuals harbor a diverse population of HIV variants and very recent
evidence suggests that the specific variant that is transmitted can influence
the outcome of infection in the newly infected person. This evidence was
reported at the Keystone HIV vaccines meeting last month, where a team of
researchers from the UK documented a case where an HIV-infected individual
transmitted to two different people on the same night, with divergent outcomes (see abstract appended
below).
PLoS Pathog 6(5): e1000876. doi:10.1371/journal.ppat.1000876
HIV-1 Transmitting Couples Have Similar Viral Load
Set-Points in Rakai, Uganda
T. Déirdre Hollingsworth1, Oliver Laeyendecker2,3, George
Shirreff1, Christl A. Donnelly1, David Serwadda4,5, Maria J. Wawer5,6, Noah
Kiwanuka4,5, Fred Nalugoda5, Aleisha Collinson-Streng3, Victor Ssempijja5,
William P. Hanage7, Thomas C. Quinn2,3, Ronald H. Gray5,6, Christophe Fraser1*
1 MRC Centre for Outbreak Analysis and Modelling, Department
of Infectious Disease Epidemiology, Imperial College London, London, United
Kingdom, 2 School of Medicine, Johns Hopkins University, Baltimore, Maryland,
United States of America, 3 National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Baltimore, Maryland, United States of
America, 4 School of Public Health, Makerere University, Kampala, Uganda, 5
Rakai Health Science Program, Entebbe, Uganda, 6 Bloomberg School of Public
Health, Johns Hopkins University, Baltimore, Maryland, United States of
America, 7 Department of Infectious Disease Epidemiology, Imperial College
London, London, United Kingdom
Abstract
It has been hypothesized that HIV-1 viral load set-point is
a surrogate measure of HIV-1 viral virulence, and that it may be subject to
natural selection in the human host population. A key test of this hypothesis
is whether viral load set-points are correlated between transmitting
individuals and those acquiring infection. We retrospectively identified 112
heterosexual HIV-discordant couples enrolled in a cohort in Rakai, Uganda, in
which HIV transmission was suspected and viral load set-point was established.
In addition, sequence data was available to establish transmission by genetic
linkage for 57 of these couples. Sex, age, viral subtype, index partner, and
self-reported genital ulcer disease status (GUD) were known. Using ANOVA, we
estimated the proportion of variance in viral load set-points which was
explained by the similarity within couples (the ‘couple effect’). Individuals
with suspected intra-couple transmission (97 couples) had similar viral load
set-points (p = 0.054 single factor model, p = 0.0057 adjusted) and the couple
effect explained 16% of variance in viral loads (23% adjusted). The analysis
was repeated for a subset of 29 couples with strong genetic support for transmission.
The couple effect was the major determinant of viral load set-point (p = 0.067
single factor, and p = 0.036 adjusted) and the size of the effect was 27% (37%
adjusted). Individuals within epidemiologically linked couples with genetic
support for transmission had similar viral load set-points. The most
parsimonious explanation is that this is due to shared characteristics of the
transmitted virus, a finding which sheds light on both the role of viral
factors in HIV-1 pathogenesis and on the evolution of the virus.
AIDS: 24 April 2010 – Volume 24 – Issue 7 – p 941–945
doi: 10.1097/QAD.0b013e328337b12e
Basic Science
HIV RNA level in early infection is predicted by viral load
in the transmission source
Hecht, Frederick M; Hartogensis, Wendy; Bragg, Larry;
Bacchetti, Peter; Atchison, Robert; Grant, Robert; Barbour, Jason; Deeks,
Steven G
Abstract
Objective: HIV-1 viral load in early infection predicts the
risk of subsequent disease progression but the factors responsible for the
differences between individuals in viral load during this period have not been
fully identified. We sought to determine the relationship between HIV-1 RNA
levels in the source partner and recently infected recipient partners within
transmission pairs.
Methods: We recruited donor partners of persons who
presented with acute or recent (<6 months) HIV infection. Transmission was
confirmed by phylogenetic comparison of virus sequence in the donor and
recipient partners. We compared viral load in the donor partner and the
recipient in the first 6 months of HIV infection.
Results: We identified 24 transmission pairs. The median
estimated time from infection to evaluation in acutely/recently infected
recipient individuals was 72 days. The viral load in the donor was closely
associated with viral load at presentation in the recipient case (r = 0.55, P =
0.006).
Conclusion: The strong correlation between HIV-1 RNA levels
within HIV transmission pairs indicates that virus characteristics are an
important determinant of viral load in early HIV infection.
Keystone Symposia: HIV Vaccines (X5), March 21-26, 2010,
Banff, Alberta, Canada
ABSTRACT NUMBER: 144
Sexual transmission of highly-distinct HIV-1 variants from a
single donor to two recipients on the same night: divergent immune recognition
and clinical outcomes
Suzanne English1*, David Bonsall2*, Aris Katzourakis, Peter
Flanagan, Anna Duda, Sara Fidler, Jonathan Weber, Myra McClure, Rodney
Phillips, John Frater and the SPARTAC trial investigators. 1. Nuffield
Department of Clinical Medicine, Peter Medawar Building for Pathogen Research,
University of Oxford, South Parks Road, Oxford, OX1 3SY, UK. 2. Faculty of
Medicine, Imperial College London, St. Mary’s Campus, Norfolk Place, London W2
1PG, UK. *Contributed equally.
It is important for vaccine development to understand why a
particular variant is transmitted and how it impacts on clinical progression.
Here we report a highly unusual case of two MSM (P1 and P2) infected with HIV-1
clade B by a third party on the same night, and their different clinical
progression, Samples were taken at 71 days post-infection (baseline). P1 and P2
were treatment naïve. No donor sample was available.
Although phylogenetics supported a single donor (baseline gag inter-host distance 1%, env and gag bootstrap
100%), remarkably different viruses were transmitted to the two recipients;
single genome amplification env sequences
from P1 and P2 were separated by a distance equivalent to at least 3.6 years of
within-host evolution prior to transmission (intra-host vs inter-host distance
0.68% within P1 and P2 vs 6.4%).
Viral load was lower in P1 than P2 (5.0 x105 vs 1.0 x106
copies/ml) and CD4+ higher (570 vs 280 cells ml).
This was associated with broader gag-directed
CD8+ ELISpot response in P1 than P2 (3 peptides vs 1 peptide) and a narrower env response (0 vs 2 peptides).
Viruses pseudotyped with env
derived from P1 were 5 times more infectious in vitro than P2. This
correlated with fewer potential N-linked glycosylation sites in gp120 (average
24 vs 28) and longer V1V2 length (average 88 vs 84 aa). There was no autologous
or heterologous neutralizing antibody activity (IC50<20).
HIV-1 preventative vaccine development must consider that
very different viruses can be transmitted from a single donor, with divergent
infectivity, immune recognition and disease progression.
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