Understanding control of HIV replication in the absence of therapy
Richard Jefferys, TAG
Individuals who maintain control of HIV replication in the absence of any therapy may offer important clues to aid the development of both vaccines and novel immune-based therapies. Many research groups are studying such individuals, with the largest and most ambitious research project being the elite controller study helmed by Bruce Walker from Partners AIDS Research Center in Boston. 
In a recent issue of the Journal of Infectious Diseases, lead investigator Florence Pereyra and colleagues report preliminary data from 126 individuals who have enrolled into the study. 
Participants are divided into two categories: elite controllers, defined as those with viral load consistently below 50 copies/mL (the limit of detection for the viral load test) and viremic controllers, whose viral loads are consistently below 2000 copies/mL. The JID paper contains data on 66 individuals in the former category and 60 in the latter; 30 individuals with chronic, progressive infection recruited over the same time period are also included for comparative purposes.
The major finding is that controllers (both elite and viremic) are a heterogeneous group with regard to many of the factors that previous studies have associated with viral load control. In terms of host genetics, HLA B*57 alleles were significantly overrepresented among controllers, but the researchers emphasize that the frequency of HLA B*57 was considerably lower than reported previously in smaller cohorts. When the analysis was expanded to any HLA allele that has been associated with a favorable prognosis in HIV infection, 68% of elite controllers and 60% of viremic controllers were found to carry at least one such allele, compared with 37% of the chronic progressors, leaving almost one-third of HIV controllers without any known relatively protective HLA alleles. CCR5 and CCR2 polymorphisms that have been associated with slowed disease progression were not overrepresented among controllers. Absolute CD4 counts were different between elite and viremic controllers (884 vs. 602 cells), in line with a recent paper showing that CD4 declines can still occur albeit very slowly – despite low or even undetectable viral loads.
Randomly selected subsets from each group of study participants were further evaluated for HIV-specific immune responses. In terms of CD8 T cell responses (as measured by interferon gamma ELISpot), elite controllers displayed the lowest breadth and magnitude of HIV-specific CD8 T cells. Median breadth was 15, 19 and 27 epitopes among elite controllers, viremic controllers and chronic progressors respectively while average magnitude was 5428, 6253 and 8300 spot-forming cells (SFC) per million PBMC (peripheral blood mononuclear cells). The simplistic interpretation of these data is that the CD8 T cell response cannot be important, but the broader, larger responses associated with higher viral loads are to be expected due to the persistent recruitment from the naive CD8 T cell pool that can occur in the setting of chronic infection, and because interferon gamma production is the last function to be lost by exhausted cells (so a large, broad response does not necessarily equate to an effective response).
When the researchers looked at IL-2 and interferon gamma production together, responses were significantly higher in elite controllers than viremic controllers or progressors (both for HIV-specific CD4 T cells and CD8 T cells), but there was still heterogeneity in that these responses were not detectable in some individuals. Interestingly, elite controllers had the highest ratio of IL-2+interferon-gamma-producing HIV-specific CD4 T cells to HIV-specific CD8 T cells while chronic progressors had the lowest, suggesting as have many prior studies – that CD4 T cell help plays an important, perhaps undervalued, role in the immune response to HIV. Adding to the heterogeneity, elite controllers also displayed the widest range of CD8 T cell interferon gamma ELISpot responses in terms of both breadth and magnitude, with responses ranging from 2-101 epitopes in breadth and from less than 500 SFC to over 25,000 SFC in magnitude. Despite the range of responses, the vast majority of both elite and viremic controllers displayed responses to many more CD8 T cell epitopes than have been reported to date in recipients of T cell-based HIV vaccine candidates (the average response in the recent Merck trial was to three epitopes).
Consistent with previously published studies, the HIV Gag protein was preferentially targeted among controllers. In progressors, Gag, Pol and Nef were targeted equally and more targeting of Env was observed than in controllers. The researchers also looked at neutralizing antibody responses. Plasma samples from both viremic controllers and progressors showed neutralizing activity against viruses sampled from the same groups as well as against laboratory HIV strains. There were no differences in neutralizing antibody titers between these two groups. Elite controllers had significantly lower neutralizing antibody responses overall but, again, heterogeneity was seen: some individuals had broad neutralizing antibody responses whereas others had very low or undetectable responses.
In concluding, the authors state that: although elite and viremic controllers share some immunologic features and are distinct from persons with chronic progressive infection, the elite controllers are a distinct subgroup. However, even within these groups there is substantial heterogeneity in all of the parameters studied, which suggests that there are as-yet-undefined viral or host factors or combinations of factors that contribute to this remarkable phenotype. They also cite the elite controller study linked to above and their hope that this large collaborative effort will better define the pathways that lead to durable control of HIV replication.
Two other recent studies offer additional perspectives on the same topic. In the first, Shiv Ghandi and colleagues show that the antiretroviral activity of APOBEC proteins does not appear to explain elite control of HIV replication. 
In the second, recently presented at CROI, researchers from Barbara Shackletts lab at UC Davis demonstrate that controllers have significantly more polyfunctional HIV-specific CD4 and CD8 T cells in their rectal mucosa, a novel finding indicating that analyses of additional compartments beyond the blood may add to the understanding of the elite controller phenomenon. 
- Pereyra et al. Genetic and Immunologic Heterogeneity among Persons Who Control HIV Infection in the Absence of Therapy. Journal of Infectious Diseases 2008;197:563571.
- Shiv K et al. Mediated Hypermutation in the Control of Human Immunodeficiency Virus Type 1 in Elite Suppressors. Journal of Virology, March 2008, p. 3125-3130, Vol. 82, No. 6.
- Ferre A et al. Polyfunctional HIV-specific T Cells in Rectal Mucosa of HIV Controllers. 15th CROI, Boston, 2008. Abstract 355.