In acute HIV infection, an evolutionary race is on as soon as the virus enters a person: The host makes T cells that will recognize and hopefully kill virus-infected cells; the virus mutates to make progeny that will not be recognized by the host.

Findings published in the Nov. 15, 2004, issue of the Journal of Experimental Medicine indicate that the earliest phases of the race might have a big effect on how successfully the virus is contained in the long run.

In "Determinants of HIV 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response," the authors - from the Edward Jenner Institute for Vaccine Research in Compton, UK; the University of Alabama at Birmingham; and Harvard University - report on the relationship between very early immune response to HIV infection and viral load later on. The results have implications for optimal vaccine design to prevent viral escape from killer T cells.

The researchers focused on the very earliest phase of the immune response, dividing it into three phases: acute infection, very early infection and early infection. The first blood samples were taken during the acute infection, while there was already a T-cell response but before antibodies to HIV could be detected. Two further blood samples to characterize the earliest phases were taken from each patient for up to 10 weeks following the symptom onset.

"A lot of people will lump all three phases together into the acute phase, especially when comparing it with long-term infection," Persephone Borrow, researcher at the Edward Jenner Institute for Vaccine Research and senior author of the study, told BioWorld Today. "So we were really very stringent."

The researchers investigated both the breadth of the T-cell response and the relative intensity of the immune response to different antigens in three patients at several stages in early phase HIV infection. Borrow and her colleagues focused on responses to three viral proteins that made up a large portion of the overall immune response: Env, Gag and Tat. Within those proteins, there can be immune responses to several different regions, or epitopes.

Patients then were followed for up to two years to relate the very early immune response to both the later evolution of the virus within its host and the persisting viral load - the level of virus a patient has in his or her blood in the chronic phase of the infection. At the clinical level, less is more, with better outcomes demonstrated for patients with lower viral loads.

Parallel Distributed Processing Foils Viral Escapees

The scientists found marked differences in both the breadth and the relative dominance of the initial immune response to HIV infection. Two patients had a relatively restricted immune response, with a significant T-cell response seen to fewer than 15 epitopes each. The response also was unevenly distributed between those epitopes, with less than five epitopes getting more than 90 percent of the T-cell attention. In contrast, the third patient had a significant T-cell response to 24 epitopes. That same patient also had a much more evenly distributed response between the different epitopes.

When asked whether the broader and more evenly distributed response simply could be a function of a stronger overall immune response, Borrow said that unpublished data on the overall magnitude of the three patients' immune response suggested that was not the case. However, she did acknowledge that "it's very difficult to determine. The best way to quantitate the overall immune response is a functional readout, for example, of interferon. But this is difficult to do during the earliest stage of HIV infection because all the cells are so active."

The researchers next analyzed the viral genome for sequence changes - so called escape mutations - within the epitopes over time. The functional consequence of such escape mutations, not surprisingly, is usually a reduced ability of the T cells to recognize and kill the antigen-presenting cells.

Borrow and colleagues showed that the virus did change its spots within all three patients to some extent, and the changes in the acute phase were similar. However, in the long run the virus was much better at outwitting the T cells in the patients with a narrow response, with mutations appearing in the majority of the epitopes that provoked an immune response in those patients.

In contrast, the virus in the patient with a broadly and evenly distributed T-cell response was less able to mutate in a way that foiled those T-cell responses, and showed a persisting viral load that was about one-fortieth to one-eightieth of the other patients. Though the scientists did not directly link those two findings in a cause-and-effect manner, in their paper they state that "the results are consistent with the hypothesis that the acute-phase viral escape may be one of the factors that determines the persisting viral load established in early HIV-1 infection."

In their entirety, the results suggest that HIV vaccines might be more effective if they are broad, keeping up the pressure on the virus by inducing a simultaneous response against a number of epitopes. That agrees with the results of several animal studies in monkeys, in which the virus ultimately was able to overcome narrowly designed vaccines. Borrow and colleagues are not planning on applying their findings to clinical strategies themselves, but she hopes that others will.

"Our findings help to give insight into how vaccines should be designed to mediate optimal control of HIV infection," she said. "We are not ourselves involved in developing HIV vaccines for clinical trials, but groups that are doing so may take our findings into account when designing vaccines for future clinical use."

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