Genetic and Stochastic Influences on the Interaction of Human Immunodeficiency Virus Type 1 and Cytotoxic T Lymphocytes in Identical Twins

Abstract

Human immunodeficiency virus type 1 (HIV-1) evolves in vivo under selective pressure from CD8؉ Tlymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting major histocompatibility complex molecules and the available viral epitope sequences. However, CTL are derived stochastically through the random gene rearrangements to produce T-cell receptors (TCR), and the relative impact of genetic versus stochastic processes on CTL targeting of HIV and immune-driven viral evolution is unclear. Here we evaluate identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, thereby allowing controlled comparisons of CTL targeting and viral evolution. Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.

Simian Immunodeficiency Virus SIVmac239 Infection of Major Histocompatibility Complex-Identical Cynomolgus Macaques from Mauritius

“…CTL against all four regions were detected during infection, suggesting that the variation results from CTL selective pressure. The pattern of chronic-phase epitope recognition in our animals was very similar to the twins monitored by Yang and colleagues (44). nomenon which was also noted in the twins monitored by Yang et al (44).…”

“…The pattern of chronic-phase epitope recognition in our animals was very similar to the twins monitored by Yang and colleagues (44). nomenon which was also noted in the twins monitored by Yang et al (44). Despite the similar CTL responses in these animals, plasma viremia became substantially higher in CY0113 after the first 16 weeks of infection.…”

“…This study mirrored two recent evaluations of monozygotic twins infected at the same time with the same stock of HIV (13,44). We identified four regions of SIV that accumulated variation by 16 weeks postinfection.…”

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

“…41 The kinetics of the CTL response and stochastic events related to viral mutation rate and T-cell receptor repertoire may have a more profound impact upon survival in these animals than in those that induce a more consistent CTL response. 42 Additionally, copy number variation of Mhc genes appears to influence disease progression. According to our results, the presence of more transcribed Mhc genes correlated with shorter survival time.…”

Serodiscordant twins: A case report of vertical HIV transmission during PMTCT option B+ role out

“…CTL lymphocytes and T helper cells are present in all neonates at birth. HIV specific CTL responses in HIV exposed but uninfected neonates seem to be more efficient due to the way HLA haplotypes bind and present HIV 1 epitopes [24][25][26][27]. Retrospective observational quantative.…”