Background:  The evolution of HIV is driven by host factors such as intracellular RNA editing and the selective pressure of cellular and humoral immune responses. The genetic background of the host likely plays a key role, especially in shaping the class I-restricted CD8⁺ T-cell response. However, it is unclear to what extent host genetics determines the targeting of this immune response, and the overall impact on virus evolution. Here we evaluate neonatally infected identical twins infected by a common blood transfusion source in 1983, to control for host genetic factors on virus evolution.

Methods:  HIV-1 plasma viremia, CD4 T-cell counts, and clinical events from birth in 1983 to the present were reviewed. General immunologic testing included flow cytometric analysis of T-cell subsets (including memory, naïve, and CD31⁺ CD4⁺ T cells), quantitation of T-cell receptor excision recombination circles (TREC) in PBMC, assessment of responsiveness to hepatitis A vaccination, and TCR V-beta spectratype analysis of peripheral blood CD8⁺ T-cells. HIV-1-specific CTL responses were assessed with overlapping peptides by ELISpot analysis. Proviral sequence was performed using PBMC DNA.

Results:  The clinical course was remarkably similar for both twins, including a robust response to identical HAART regimens instituted in 2000. Phenotypically, they had similar responsiveness to a neoantigen (hepatitis A vaccination), similar levels of naïve/memory T cells, and similar levels of TREC. Mapping of CTL responses demonstrated very similar epitope targeting. However, sequencing of Gag/Pol/Env/Nef revealed viruses that appear to have diverged significantly. TCR spectratyping performed using RNA from CD8⁺ T cells revealed numerous fine differences in CDR3 patterns, despite superficially similar CTL responses to HIV.

Conclusions:  Despite striking clinical similarity and shared CD8⁺ T-cell targeting, the T-cell receptor genotypes and targeted viral sequences show considerable divergence after 19 years of infection. These results indicate that while genetic factors exert considerable influence on the clinical and cellular immune phenotype, other influences result in fine immunologic differences, associated with divergent viral evolution in vivo.

Keywords: Cytotoxic T cells; Twins; evolution