Elite control of HIV infection: implications for vaccine design

Abstract

Background: 'Elite controllers' are rare HIV-infected individuals who are able to spontaneously control HIV replication without medication, maintaining viral loads that are consistently below the limits of detection by currently available commercial assays.

Objective: To examine studies of elite controllers that may elucidate mechanisms of HIV immune control useful in designing a vaccine.

Methods: Recent literature on HIV controllers and studies that have evaluated aspects of viral and host immunology that correlate with viral control are examined.

Results/conclusions: Although many elements of innate and adaptive immunity are associated with control of HIV infection, the specific mechanism(s) by which elite controllers achieve control remain undefined. Ongoing studies of elite controllers, including those examining host genetic polymorphisms, should facilitate the definition of an effective HIV-specific immune response and guide vaccine design.

Figure 1. Immune control of HIV infection

A) Prior to cell entry, antibodies produced by B cells may neutralize free virus particles, preventing cells from becoming HIV infected. B) Once a cell is infected, CTL may mount effective cytolytic responses through recognition by a unique TCR of a viral peptide presented as a complex with HLA class I on the surface of the infected cell. C) If the immune response is not successful in controlling viral replication in stages A or B, progeny virions will be produced and will bud from the infected cell, creating new virus particles that can go on to infect other cells, though these may also be limited by neutralizing antibodies

Figure 2. Effect of HLA-B alleles on CD4 decline and viral load increase over time after HIV infection

Average change in the square root CD4 counts (left side) and log viral load measurements (right side) per year and 95% confidence intervals were determined using a linear mixed effects regression (LMER). HLA-B alleles that are most to least protective are listed from top to bottom, respectively. The vertical line in the middle of each plot represents the sample average and confidence intervals for alleles deviating significantly from this value do not cross the line. Alleles shown in red are HLA-B Bw4+ , while those in black are HLA-B Bw6+. Data from both seroconverter and seroprevalent individuals were used in the analysis. Seroconversion date is used as the intercept in the LMER, but in seroprevalents, the first observed data point is used instead. P values were determined using the Wald test.

Figure 3. Heterogeneity of CTL responses in elite controllers measure by IFN-γ ELISpot

IFN- γ responses from two elite controllers measured by enzyme-linked immunosorbent spot (ELISpot) assay. While each subject was tested against. 410 peptides overlapping by 10 amino acids and spanning the whole HIV proteome, they exhibit significant differences in both the breadth and the magnitude of their responses.

Figure 4. Comparison of flow cytometric-measured HIV-specific T cell responses between an elite controller and an untreated chronic progressor

Flow analysis of Gag specific CD4+ and CD8+ T cell responses measured by intracellular cytokine staining. Dead cells are excluded from analysis by gating only on dead cell dye negative cells, CD3+ CD14/19 – cells are identified as T cells. CD4+ and CD8+ subpopulations are identified based on the presence of surface markers. The percentage of cells within the CD4+ and CD8+ subpopulations that produce Il-2, IFN-γ or both cytokines is measured for a representative elite controller and a chronic progressor.