After 20 years of focused HIV vaccine research, the development of an effective HIV preventive vaccine remains elusive. One of the main limitations has been the inability to identify immunogens that can generate broadly cross-neutralizing antibodies capable of recognizing and targeting the HIV envelope (Env) proteins. Current data support the notion that the risk of HIV transmission and disease progression is reduced at low levels of plasma HIV RNA, therefore an alternative approach is to develop vaccines that aim to reduce plasma viremia to those low levels.
Some HIV-positive individuals have been able to maintain virus load levels below the limits of detection for 30 years or longer. These individuals have been characterized in the HIV literature as HIV controllers, elite controllers and elite suppressors; they have been the main focus of ongoing research that aims to understand host, viral, and immunologic parameters that are associated with effective containment of HIV infection.
To date many factors have been associated with HIV control, but none of them have been able to fully explain this phenomenon. Probably the strongest evidence that supports a role for host genetics is the over-representation of the HLA B*57 allele and to a lesser extent the B*27 allele among HIV controllers, compared with individuals with progressive infection; still these alleles are absent in more than half of HIV controllers. How the presence of these HLA types is related to viral control is not yet understood. Other host genetic factors associated with viral control, including the CCR5 co-receptor polymorphisms have been described in this population.
Cytotoxic CD8+ T lymphocytes (CTLs) can kill HIV-infected host cells via presentation of viral antigen in the context of HLA class I molecules. The activity of these T cells and the enrichment for particular HLA class I alleles in HIV controllers caused speculation that controllers might exhibit increased magnitude or breadth of the CTL response to HIV, compared to individuals with chronic progressive infection. Studies have not supported this theory. Instead, the quality of the CTLs - as measured by their ability to secrete multiple cytokines and to proliferate upon antigen stimulation - may be more important for viral control than higher CTL frequency.
It has also been described that the protein specificity of these CTLs may play a role in effective immune control of HIV. Specifically, preferential targeting of the HIV Gag protein has been associated with lower viral loads. The role of CD4 helper T cells in HIV control continues to be another focus of intense investigation. Polyfunctionality and reduced expression of inhibitory molecules like CTLA-4 and PD1 in this cell population have been described in HIV controllers.
Regarding the HIV virus itself, earlier studies documented slowed progression of disease in association with nef-deleted HIV mutants. However recent studies suggest that most cases of spontaneous HIV control are unlikely to be explained by HIV genetic defects.
We believe that HIV controllers can provide key insights for vaccine design. Many lessons can be learned from elucidating the mechanisms behind this phenotype. Advances on the human genetics front now allow for rapid automated analysis using single nucleotide polymorphisms as genetic signatures.
The International HIV Controllers Study aims to perform a genome wide association study to determine the influence of genetic factors on innate and adaptive immunity on durable suppression of HIV.
HIV Controllers Genome Wide Association Study (GWAS) Results ToolÂ