CTL Escape and Viral Fitness in HIV/SIV Infection

Sayuri Seki,Tetsuro Matano

doi:10.3389/fmicb.2011.00267

Abstract

Cytotoxic T lymphocyte (CTL) responses exert a suppressive effect on HIV and simian immunodeficiency virus (SIV) replication. Under the CTL pressure, viral CTL escape mutations are frequently selected with viral fitness costs. Viruses with such CTL escape mutations often need additional viral genome mutations for recovery of viral fitness. Persistent HIV/SIV infection sometimes shows replacement of a CTL escape mutation with an alternative escape mutation toward higher viral fitness. Thus, multiple viral genome changes under CTL pressure are observed in the chronic phase of HIV/SIV infection. HIV/SIV transmission to HLA/MHC-mismatched hosts drives further viral genome changes including additional CTL escape mutations and reversions under different CTL pressure. Understanding of viral structure/function and host CTL responses would contribute to prediction of HIV evolution and control of HIV prevalence.

Highlights

Virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses play a central role in the control of HIV and simian immunodeficiency virus (SIV) replication (Borrow et al, 1994; Koup et al, 1994; Matano et al, 1998; Jin et al, 1999; Schmitz et al, 1999; Goulder and Watkins, 2008)
SIVmac239Gag216S244E247L312V373T carrying five gag mutations had lower replicative ability in vitro compared to SIVmac239Gag216S244E373T carrying three gag mutations. These results suggest that selection of CTL escape mutations even with viral fitness costs could be advantageous for viral replication in vivo under CTL pressure
We examined viral genome changes after challenge of 90-120-Ia-negative macaques with SIVs carrying multiple CTL escape mutations selected in 90-120-Ia-positive macaques

Summary

Introduction

Virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses play a central role in the control of HIV and simian immunodeficiency virus (SIV) replication (Borrow et al, 1994; Koup et al, 1994; Matano et al, 1998; Jin et al, 1999; Schmitz et al, 1999; Goulder and Watkins, 2008). Gag206–216 (IINEEAADWDL) epitope-specific CTL responses exert a suppressive effect on SIV replication and select for a CTL escape mutation, GagL216S, leading to a leucine (L)-to-serine (S) substitution at the 216th amino acid (aa) in Gag capsid (CA) with viral fitness costs (Kobayashi et al, 2005). SIVsmE543-3 has a different amino acid (glutamate [E]) from SIVmac239 (aspartate [D]) at Gag residue 205, and this GagD205E change resulted in escape from Gag206–216-specific CTL recognition, leading to failure in control of SIVsmE5433 replication in 90-120-Ia-positive vaccinees (Moriya et al, 2008).

Results

Conclusion