Long-term non-progressors (LNTP) remain a valuable resource for teasing out the precise components of the immune system responsible for keeping HIV infection at bay. In all of Europe, the laboratory group that is, arguably, in hottest pursuit of the missing pieces to this immunological puzzle is Paris-based doctor Brigitte Autran. Richard Jefferys reports on the status of her group's work -- and hints at what new discoveries we might expect later in the year.
Renowned Parisian immunologist Brigitte Autran helped kick off the first full day of this year's retrovirus conference with a half-hour plenary on immune reconstitution and correlates of long-term non-progression. Autran began by reviewing seminal work from her group at the Hôpital Pitié-Salpêtrière, originally published in the journal Science in 1997. These studies described the rapid redistribution of mainly memory CD4 T cells from the lymph nodes after HAART initiation, accompanied by a precipitous decline in markers of immune activation and followed by a slow but steady increase of naïve T cells over subsequent years. Concomitant improvements in T-cell responses to common opportunistic pathogens were also reported. All of Autran's initial observations regarding HAART-induced immune reconstitution have since been confirmed and extended by other research groups.
The one type of immune response that is typically absent or weak in HAART-treated individuals is HIV-specific; CD4 T-cell responses to the virus can be hard to detect and, if detectable, may be functionally compromised. CD8 T-cell responses are typically detectable but also show evidence of functional defects and appear unable to keep pace with viral evolution. The new research priority for Autran's group is to ascertain whether this apparent deficit in HIV-specific immunity can be addressed with therapy. As a first step, a cohort of long-term non-progressors (LTNP) was analyzed in order to try and define clear correlates of immunologic control of HIV infection. No factors related to the infecting virus were identified, but a number of associations relating to the immune response emerged.
As reported by others, certain class I and II HLA genotypes are more common in LTNP, suggesting that the ability of both CD8 and CD4 T cells to recognize and respond to HIV is a key variable influencing the outcome of infection. Using an ELISpot assay to identify HIV-specific CD8 T cells based on their ability to produce interferon-gamma, Autran reported that stronger and more broadly targeted responses were detected in LTNP compared to progressors, although this finding has not been duplicated by some groups. Autran also looked at the expression of the cell-killing enzyme perforin in HIV-specific CD8 T cells and found that fewer cells were perforin-positive in LTNP than people with progressing disease, indicating that this is not a useful correlate (as previous study results had suggested).
Turning to HIV-specific CD4 T cells, the correlation between the proliferative response to p24 and control of viral load in Autran's study was highly significant. A similar link was seen when, instead of proliferation, the frequency of CD4 T cells making interferon-gamma in response to p24 was measured by ELISpot. Since other studies have found that the frequency of HIV-specific CD4 T cells (as measured by ELISpot) is not always correlated with control of viral load, Autran's group identified another marker that may address the functionality of the CD4 T-cell response.
Interferon-gamma production is typically associated with a type of CD4 T-cell response known as T-helper type 1 or Th1, considered to be important in the defense against many viral infections, including HIV. It is known from basic immunology research that Th1 responses drive B-cells to make a particular class of antibody called IgG2. Although many studies have measured HIV-specific antibodies in infected individuals, Autran's colleague Nicole Ngo-Giang-Houng looked specifically for those belonging to the IgG2 subclass, reasoning that they might be a marker for robust, Th1-type HIV-specific CD4 T-cell activity. As reported last year, she found that IgG2 antibodies targeting HIV's gp41 protein were strongly associated with persistent LTNP status. Perhaps surprisingly, the presence of these antibodies was not linked to an ability to neutralize two primary isolates or the lab strain HIV-LAI.
Autran updated these findings at the Seattle retrovirus conference by assessing whether maintenance of LTNP status (over five years of follow-up subsequent to study entry) could be predicted by combining the IgG2 and ELISpot CD4 T-cell results. The analysis revealed that a strong HIV-specific CD4 T-cell response (over 170 spot-forming units or SFC in the ELISpot test) and the presence of IgG2 antibodies directed against gp41 correlated strictly with LTNP status. One hundred percent of individuals with these responses maintained their non-progressor status over five years of follow-up. In contrast, more than half the individuals with the same HIV-specific CD4 T-cell response but no gp41-specific IgG2 antibodies experienced disease progression during this period. Over 80% of the individuals in the remaining two categories (those with gp41-specific IgG2 antibodies but lacking a strong HIV-specific CD4 T-cell response and those with neither IgG2 nor a strong CD4 T-cell response) developed progressive disease.
Having outlined the immune responses that may protect against progression, Autran described the strategies her research team is employing to try and create (or boost) the same type of HIV-specific immunity in people with acute and chronic HIV infection. The current goals are straightforward: to use candidate vaccines in conjunction with HAART in order to induce strong, broad and durable HIV-specific CD4 and CD8 T-cell responses, in the hope of reducing the viral load "set point" when HAART is stopped and thus extending the time that drug therapy can safely be withheld.
A number of studies are under way (see table below) using just about every vaccine that's been shown to be safe and to induce at least a meager level of HIV-specific T-cell activity: ALVAC, lipopeptides and Remune. Autran coyly referred to "encouraging intermediate results" from these studies, which indicate that new HIV-specific CD4 T-cell responses can be induced in both primary and chronic infection. She reported that the frequencies of these responses are comparable to LTNP in vaccinated individuals with primary infection, but are slightly lower in study participants with chronic infection. CD8 T-cell data are still pending. Additional trials are now being planned with newer and potentially more immunogenic vaccines such as Merck's DNA/adenovirus combination product.
|Study||Vaccine||Stage of Infection|
|ANRS 094||ALVAC vCP1433 (gag, env, epitopes from nef and RT)||Chronic|
|ANRS 093||ALVAC vCP1433 + lipopeptides + IL-2||Chronic|
|ANRS 095||ALVAC vCP1433 + lipopeptides + IL-2||Acute|
|QUEST||ALVAC vCP1452 (gag, env, pro, epitopes from nef and RT) +/- Remune||Acute|
|Source: Autran, 9CROI, 02/02|