Selective Escape from CD8 ⁺ T-Cell Responses Represents a Major Driving Force of Human Immunodeficiency Virus Type 1 (HIV-1) Sequence Diversity and Reveals Constraints on HIV-1 Evolution

Abstract

The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8؉ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8؉ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8 ؉ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.

Dendritic cell based vaccines for HIV infection

“…It could be argued that HIV has already escaped to the immune system of the patient so boosting with the same virus will not improve the breadth of the immune response and would not be effective. However, although it is true that viral escape to CTL has been extensively demonstrated, [30][31][32][33] some data suggest that the antigen-presenting functions of dendritic cells are impaired in HIV-1 infected patients and this could contribute to the functional defects of HIV-1-specific helper and CTL responses. 34,35 We think that our model could help to know if a correct antigen presentation with this therapeutic vaccine could reverse the functional defect of helper and CTL responses and prevent, at least partially, the viral escape.…”

Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 + T cells and reduces chronic retroviral set points

“…T he ability of viruses to establish chronic infections requires one or more mechanisms to escape the destruction of infected cells by CD8 + cytotoxic T lymphocytes (CTLs) (1,2). One such mechanism appears to be the induction of regulatory T cells (Tregs), a specialized subset of CD4-expressing T cells that can suppress the proliferation and/or function of effector T cells (3).…”

Control of Simian Immunodeficiency Virus SIVmac239 Is Not Predicted by Inheritance of Mamu-B * 17 -Containing Haplotypes

“…Though many groups have examined proviral SIV (23) and HIV (1,20) sequences from individuals who control virus, the relationship between these sequences and replicating virus is questionable (2). We coupled ultrasensitive viral RNA extraction with reverse transcription-PCR using amplification primers flanking the Nef IW9 epitope sequence to extract viral sequence from plasma virus.…”