The research group of Francis Plummer at the University of
Manitoba was among the first to document evidence that some people can resist
HIV infection despite multiple exposures. The evidence derives from a cohort of female sex workers in
the Pumwani district of Nairobi; around 10% of the more than 1,000 women in the
cohort have remained HIV negative despite ongoing exposures and a number of
genetic and immunological factors have been described that associate with this
apparent resistance to infection. Among these factors are certain class I &
II HLA genes and HIV-specific CD8 T cell responses (which have been detected in
both the cervix and peripheral blood despite the absence of any detectable
virus).
However, some of the women once thought to be resistant have
seroconverted many years after first joining the cohort. In one published study, the most significant risk factor for this “late
seroconversion” was taking a break from sex work, suggesting that at least in
some women, ongoing exposure to HIV was involved in the maintenance of
resistance (although the study also described some women who, after taking a
break and returning to sex work, experienced an increase in their HIV-specific
CD8 T cell responses and did not become infected). One lingering question
regarding these observations is whether women who have developed HIV-specific
CD8 T cell responses prior to becoming infected are able to better control
viral replication after infection occurs; in other words, does the presence of
HIV-specific CD8 T cells give the immune system any kind of head start against
the virus?
Although this is a difficult question to answer in a cohort
study, Plummer’s group has now published data suggesting that pre-infection
HIV-specific CD8 T cells may indeed be linked to better control of viral load
post-infection. Because the numbers of people studied were small,
the researchers conducted two analyses, one involving the Nairobi cohort and
another with a different cohort in Kibera. In both cases, women who displayed
HIV-specific CD8 T cell responses prior to infection had lower post-infection
viral loads on average (by around 1 log) compared to women who lacked these
responses. The researchers stress that all the pre-acquisition immunological
assays were performed by investigators who were blinded to subsequent HIV
acquisition status and viral load. In terms of the functionality of
HIV-specific CD8 T cells between the two groups, the ability of the cells to
proliferate in response to HIV antigens associated with better viral load
control, while numbers of HIV-specific CD8 T cells producing the cytokine
interferon gamma showed the opposite trend.
In discussing the study results, the researchers point out
that while it’s possible that pre-infection HIV-specific CD8 T cells played a
causal role in the observed outcomes, they could also represent a marker for
other genetic and/or immune factors that are linked to better control of HIV replication.
They nevertheless argue that their data support continued evaluation of T cell-based
vaccines despite the disappointing results obtained with Merck’s candidate.
AIDS: POST AUTHOR CORRECTIONS, 27 April 2010
doi: 10.1097/QAD.0b013e3283391d40
Concise Communication: PDF Only
Kaul, Rupert; MacDonald, Kelly S; Nagelkerke, Nico J;
Kimani, Joshua; Fowke, Keith; Ball, T Blake; Luo, Ma; Kariri, Anthony; Jaoko,
Walter; Moses, Stephen; Rowland-Jones, Sarah; Plummer, Francis A
Published Ahead-of-Print
Abstract
Objective: Vaccine-induced CD8+ T-cell responses in primates
have been associated with a reduced simian immunodeficiency virus plasma viral
load and enhanced T-cell responses, but cellular vaccines have shown limited
success in human trials. We previously described HIV-specific T-cell responses
in two groups of highly exposed, persistently seronegative Kenyan female sex
workers, and a subset of these participants have subsequently acquired HIV. We
examined the impact of pre-existing CD8+ T-cell responses on post-acquisition
outcomes.
Design and methods: HIV-specific CD8+ T-cell responses had
been examined in highly exposed, persistently seronegative participants from
the Pumwani and Kibera cohorts, using a combination of virus-specific lysis,
proliferation, interferon-gamma production, or all. Plasma viral load set point
and HIV-specific T-cell proliferation and cytokine production were now examined
post hoc by blinded investigators in the subset of participants who acquired
HIV.
Results: Pre-acquisition cellular immune assays and
post-infection viral load were available for 46 participants, and HIV-specific
CD8+ T-cell responses had been detected in 25 of 46 (54%) participants.
Pre-acquisition CD8+ T-cell responses were associated with a lower
post-acquisition HIV viral load set point in both cohorts (pooled analysis, 3.1
vs. 4.1 log10 RNA copies/ml; P = 0.0002) and with enhanced post-acquisition HIV-specific
CD8+ T-cell proliferation (3.8 vs. 1.0%, P = 0.03), but with a trend to reduced
post-acquisition CD8+ T-cell interferon-gamma responses.
Conclusion: HIV-specific CD8+ T-cell responses prior to HIV
acquisition were associated with a lower HIV viral load and an altered
functional profile of post-acquisition CD8+ T-cell responses.
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