The Presence of Anti-Tat Antibodies Is Predictive of Long-Term Non Progression to AIDS or Severe Immunodeficiency

Tat is a regulatory protein of HIV that is expressed very early after infection and is essential for virus gene expression, replication, and transmission. Several studies have suggested that an immune response to Tat may play a role in the control of HIV disease progression.

The results of preclinical studies with anti-HIV Tat-based vaccines have supported this concept: vaccination has been shown to be safe and to induce specific immune responses capable of containing virus replication in monkeys and mice, and vaccination has been shown to prevent disease after pathogenic virus challenge in monkeys.

On the basis of these results, preventive and therapeutic phase 1 clinical trials with the native Tat protein are ongoing in Italy. In the present study, to identify immune responses that may be predictive of HIV disease progression, researchers evaluated the prognostic value of anti-Tat antibodies in a cohort of 252 subjects with estimated dates of HIV-1 seroconversion both before and after introduction of HAART.

Results

· The study population consisted of 252 HIV-1–positive subjects; 166 (65.9%) were men and 86 (34.1%) were women. The median follow-up time was 7.2 years. The median age was 28 years (range, 17–68 years).

· Of the 252 subjects, 30 (11.9%) were anti-Tat positive; anti-Tat antibodies were detected at a median of 4.1 years after HIV-1 seroconversion.

· Of the 252 subjects, 95 progressed to AIDS-defining illnesses (48 subjects) or CD4+ T cell counts of < or = 200 cells/microliter (47 subjects).

· The cumulative incidence of clinical or immunological AIDS events 10 years after HIV seroconversion was 26.1 events/1000 p-y in the anti-Tat–positive subjects and 53.9 events/1000 p-y in the anti-Tat–negative subjects, and this lower incidence in the anti-Tat–positive subjects was statistically significant (P = .016).

· The median survival times were 12 and 9 years for the anti-Tat–positive and anti-Tat–negative subjects, respectively.

In summary, the authors write

· The risk of progression was lower in the anti-Tat–positive subjects than in the anti-Tat–negative subjects.

· Progression was faster in the persistently anti-Tat-negative subjects than in the transiently anti-Tat–positive subjects, and

· No progression was observed in the persistently anti-Tat–positive subjects.

Discussion

The results of the present study reveal a strong association between the presence of anti-Tat antibodies and a slower progression to clinical and immunological (AIDS-defining) end points. After adjustment for age and calendar year, the anti-Tat–positive subjects in this study had a 60% lower risk of disease progression, compared with the anti-Tat–negative subjects.

The analysis of the subjects with sequential serum samples indicated that the persistently anti-Tat–positive subjects had the lowest risk of disease progression, whereas the persistently anti-Tat–negative subjects had the highest risk of disease progression.

“Furthermore,” note the authors, “the transiently anti-Tat–positive subjects had a nearly 70% lower risk of progression, compared with the persistently anti-Tat–negative subjects. These results provide evidence that the presence of anti-Tat antibodies is a good predictor of slower progression of HIV disease.”

Conclusions

In conclusion, the authors write:

· The presence of anti-Tat antibodies is a predictor of slower HIV disease progression. The association remains after adjustment for calendar year, considered as a proxy for the introduction of HAART.

· The issue of whether anti-Tat antibodies play a direct protective role or are only an indirect marker of protection merits further investigation.

· Nevertheless, in concert with the assessment of cell-mediated immunity (T helper cells and CTLs), anti-Tat antibodies may be a valuable tool with which to monitor the immunogenicity of Tat-based vaccines during advanced clinical testing.

04/06/05

Reference
G Rezza and others. The Presence of Anti-Tat Antibodies Is Predictive of Long-Term Nonprogression to AIDS or Severe Immunodeficiency: Findings in a Cohort of HIV-1 Seroconverters. The Journal of Infectious Diseases 191(8): 1321-1324. April 15, 2005.