HIV-1 variation diminishes CD4 T lymphocyte recognition

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Effective antiviral immunity relies on cytotoxic T lymphocytes and CD4(+) T lymphocyte help.
• Failure of T helper responses is a key factor in viral persistence.
• Human Immunodeficiency Virus type 1 (HIV-1) infection often involves complex immune evasion strategies.

Purpose of the Study:

• To investigate whether variations in HIV-1 CD4(+) T helper epitopes contribute to viral persistence.
• To identify specific HIV-1 epitopes and their natural variants.
• To assess the impact of these variations on T lymphocyte responses.

Main Methods:

• Assayed peripheral blood mononuclear cells from 43 asymptomatic HIV-1(+) patients for proliferative responses to HIV-1 antigens.
• Mapped dominant epitopes in two individuals to p24 Gag and p17 Gag, restricted by HLA-DR1 and HLA-DRB52c respectively.
• Analyzed naturally occurring variants of identified epitopes in proviral DNA and assessed their binding and stimulatory capacity.

Main Results:

• 12% of patients showed positive proliferative responses to HIV-1 antigens.
• Nine naturally occurring variants of the p24 Gag epitope were identified, all binding to HLA-DR1, but three failed to stimulate a CD4(+) T lymphocyte line.
• Variant antigens arising in HIV-1(+) patients can fail to stimulate T cell receptors of HLA class II-restricted lymphocytes, despite successful presentation.
• Variants also failed to stimulate fresh, uncultured cells, unlike the original peptide.

Conclusions:

• Naturally occurring variants of HIV-1 epitopes can arise that are not recognized by the circulating T lymphocyte repertoire.
• These altered peptide ligands may curtail crucial CD4(+) T lymphocyte helper responses.
• This immune evasion mechanism could contribute to viral persistence in HIV-1 infection, particularly where variant viruses are prevalent.