Summary auto-generated
This study examined whether cytotoxic T lymphocyte (CTL) responses against different HIV-1 proteins predict disease progression rates. Researchers analyzed CTL precursor frequencies in twelve HIV-1-infected individuals: seven long-term asymptomatics (LTA) who remained AIDS-free for over a decade and five rapid progressors who developed AIDS within 3-6 years. Using limiting dilution assays with vaccinia virus-infected cells expressing different HIV-1 proteins (Gag, RT, Nef, Rev, Tat), they measured CTL responses early in infection and during follow-up. The key finding was that Rev-specific and Tat-specific CTL precursors were detected predominantly in LTA individuals and were essentially absent in progressors, with statistically significant differences. In contrast, CTL responses against structural proteins Gag and RT, or the regulatory protein Nef, were similar between both groups. Early Rev-specific CTL responses within 24 months of seroconversion correlated with slower disease progression. The authors suggest that CTL targeting early, regulatory proteins like Rev and Tat may be more protective than responses against structural proteins, possibly because these proteins are expressed early in the viral replication cycle and in latently infected cells.
Key findings
- Rev-specific and Tat-specific CTL precursor frequencies were significantly higher in long-term asymptomatics compared to rapid progressors, with Mann-Whitney p<0.05
- Early detection of Rev-specific CTL within 24 months after seroconversion was associated with slower disease progression (p<0.02)
- CTL responses against structural proteins (Gag, RT) and Nef showed no significant differences between slow progressors and rapid progressors
- Viral sequence analysis revealed differences in HLA peptide-binding motifs of Rev between a long-term asymptomatic and rapid progressor with identical HLA types, suggesting viral variation impacts CTL epitope generation
- The absence of Rev and Tat-specific CTL responses in progressors was not due to general CTL failure, as responses to other viral proteins remained stable or increased
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Abstract
Immunological correlates of AIDS-free survival after human immunodeficiency virus type 1 (HIV-1) infection are largely unknown. Cytotoxic T lymphocyte (CTL) responses are generally believed to be a major component of protective immunity against viral infections. However, the relationship between HIV-1-specific CTL responses and disease progression rate is presently unclear. Here we show in twelve HIV-1-infected individuals that detection of Rev-specific CTL precursors (CTLp) early in the asymptomatic stage, as well as detection of Rev- and Tat-specific CTLp later during follow-up, inversely correlate with rapid disease progression. No such correlation was found for detection of CTLp against Gag, RT or Nef. Further studies are required to determine whether a protective mechanism is indeed the basis of the observed correlation. The data presented are in agreement with the hypothesis that CTL against proteins that are important for early viral transcription and translation are of particular importance in protection from rapid disease progression.