Cytotoxic T-Lymphocyte Responses to HIV-1 Reverse Transcriptase (Review)

Abstract

Cytotoxic T lymphocytes (CTL) play an important role in the control of human immunodeficiency virus (HIV) infection. CTL responses have been demonstrated for most of the HIV gene products, predominantly gag, pol, and env-encoded proteins, and also for the regulatory proteins Nef, Tat, Vif, or Rev. The HIV-1 reverse transcriptase (RT), which derives from expression of the pol gene, is an important target of cellular immune responses in infected individuals. More than 40 different peptides containing RT-specific CTL epitopes have been identified. The most conserved and frequently detected are located in the 'fingers' and 'palm' subdomains of the enzyme, but other epitopes have been found in the 'thumb' and 'connection' subdomains as well as in the RNase H domain. Studies on the sequence variability and functional role of amino acids forming CTL epitopes are relevant for addressing important questions relative to viral escape from immmune control and the future design of anti-AIDS vaccines.

Vaccine-Induced Immune Responses in Rodents and Nonhuman Primates by Use of a Humanized Human Immunodeficiency Virus Type 1 pol Gene

“…Finally, this synthetic gene represents a valid immunogen, whose intracellular processing can be altered and which can be incorporated into any nonreplicating viral vector system (or combination thereof) to optimize host immunity. As increasing numbers of Pol T-cell epitopes are identified in seropositive human subjects (26,35), it becomes apparent that the inclusion of a pol component in an HIV vaccine will improve the breadth of the cellular immune responses and will increase the likelihood of establishing protection against an HIV infection. …”

“…As the product of the largest structural gene in the HIV genome, it contains many T-cell epitopes. In fact, Pol-specific T-cell responses have been identified in infected HIV-1 patients with very high incidence (21), and over 60 CTL epitopes have been reported thus far (26,35). For these reasons, Pol would be integral to a vaccine that is capable of inducing potent, broad cellular immunity against HIV.…”

Conservation of functional domains and limited heterogeneity of HIV-1 reverse transcriptase gene following vertical transmission

“…Strong CTL responses are maintained in long-term nonprogressors and these responses correlate with decrease in viral load [51-55]. It has been shown that transmitting mothers have larger numbers of CTL escape variants as compared to non-transmitting mothers [56], emphasizing that CTL escape variants may become a part of circulating virus that influences vertical transmission [56,57]. Several regions in the RT gene have been shown to elicit strong CTL responses during HIV-1 infection.…”

Differences in Evolution of HIV-1 Subtype C Reverse Transcriptase Between Children and Adults Likely Explained by Maturity of Cytotoxic T-Lymphocyte Responses

“…3 The reverse transcriptase (RT) protein of HIV-1 is an important target of CTL responses in infected individuals, 4 and more than 40 different RT-specific CTL epitopes have been identified. 4 The RT enzyme is also a target for most approved antiretroviral therapies, 5 and similar to CTL evasion, selection for genetic mutations in HIV-1 RT decreases the susceptibility to these antiretroviral therapies.…”

“…3 The reverse transcriptase (RT) protein of HIV-1 is an important target of CTL responses in infected individuals, 4 and more than 40 different RT-specific CTL epitopes have been identified. 4 The RT enzyme is also a target for most approved antiretroviral therapies, 5 and similar to CTL evasion, selection for genetic mutations in HIV-1 RT decreases the susceptibility to these antiretroviral therapies. 5 Understanding the antigenicity, immunogenicity, and evolution of CTL epitopes that incorporate antiretroviral (ART) drug resistance mutations (DRM) is perhaps a first step toward developing immune strategies against the emergence and transmission of drug-resistant HIV strains.…”