The exact difference between long-term nonprogressors (LTNPs) and those with progressive HIV remains ill defined. The study of the differences in immune response is dependent on the technology available for their detection. A central difficulty has been tracking down and measuring the activity of the CD4+ T-helper cells that respond to HIV infection. These cells, themselves the main target of HIV, orchestrate production of cells that create antibodies (B-cells) or that kill HIV-infected cells (CTLs).

It is now possible to evaluate this population of CD4+ cells using a variety of techniques, but the newly available assays raise as many questions as they answer. Two recent studies reported the first findings of these assays. One was presented by a team from the National Institute for Allergy (A. McNeil et al. 13^th International AIDS Conference. poster MoPpA1002) and the other from the Imperial College School of Medicine in London (JD Wilson et al. J Infect Dis 2000 Sep;182(3):792-8.

Both groups first detected anti-HIV CD4+ T-helper cells in assays that measured the levels of stimulating cytokine after exposure to HIV antigens. They observed that surprising numbers of these cells survive in most untreated persons with chronic progressive infection. In the average person with chronic progression, the anti-HIV T-helper cells appear dysfunctional because they are unable to proliferate when exposed to HIV antigens in test-tube assays. The same cells from LTNPs prove highly active in such proliferative assays.

The NIAID group took this research a step further and watched what happened to eight persons who were successively treated during chronic infection and then underwent a treatment interruption. As viral loads soared from below 50 copies/mL in blood plasma to 5,000 to 100,000 copies/mL, the number of anti-HIV CD4+ T-helper cells first increased as measured by cytokine production, but their ability to proliferate ultimately plummeted.

Mark Connors of the NIAID group explained, “There has been an association established between T-helper activity and control of HIV, but an association does not prove cause and effect. Our paper suggests that cause and effect is the other way around. High HIV diminishes the proliferative response, which causes loss of control of viral replication.” Connors noted that in the end, the process may be more circular. Breakthrough HIV suppresses the immune defense, allowing HIV levels to rise further and escape any possibility of resuppression without drugs.

It is noteworthy that T-helper cell proliferation in anti-HIV assays fell sharply in the five Massachusetts General patients with high HIV rebounds after their first and second treatment interruptions. In between the two interruptions, proliferation returned and may have improved somewhat, followed by an increase in viral control during the second interruption.

In the NIAID study, T-helper cell proliferation during the treatment interruption could be restored by the addition of anti-CD28 antibody to the assay cell cultures. Anti-CD28 fits into the CD28 receptor on the surface of T-helper cells. This receptor helps stimulate T-helper cells during interactions with antigen-presenting cells such as macrophages and dendritic cells. Antigen-presenting cells scavenge the body for foreign proteins, which they break up into the specific epitopes they use to excite the T-helper and CTL cells that specialize in erecting immune defenses. Macrophages and dendritic cells, which themselves are susceptible to HIV, may become dysfunctional during HIV infection. This dysfunction could be at the heart of the failure of anti-HIV T-helper cells to proliferate when faced with significant HIV levels.

Connors refused to speculate on the mechanisms involved in suppressing proliferative responses and their rescue by anti-CD28. Nonetheless, the results of the NIAID and British studies throw into question the value of therapeutic vaccines as an adjunctive treatment in chronic infection. It may be that these vaccines generate an immune response, but that response will not work well if HIV rebounds, either on its own or during treatment interruptions. Improvements in antigen-presentation cell function may be a necessary addition – and that is another reason for the interest in dendritic cell-based vaccines mentioned in the main article.

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