Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency

Charles R. Rinaldo Jr.,1,2,* Xiao-Li Huang,1 Zheng Fan,1 Joseph B. Margolick,3 Luann Borowski,1 Aki Hoji,1 Christine Kalinyak,1 Deborah K. McMahon,1,2 Sharon A. Riddler,1,2 William H. Hildebrand,4 Richard B. Day,1 and John W. Mellors1,2,5

Graduate School of Public Health1 and School of Medicine,2 University of Pittsburgh, and the Veterans Affairs Medical Center,5 Pittsburgh, Pennsylvania 15261; Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 212053; and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 731904

Received 17 December 1999/Accepted 29 January 2000

Journal of Virology, May 2000, p. 4127-4138, Vol. 74, No. 9

The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8+ T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-) production by CD8+ T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8+ T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8+ T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8+ cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN- production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8+ CD45RO+ cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8+ T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.

I would like to add that although there has been a good deal of results from small studies suggesting that HIV-specific CTLs are key to stimualting an immune response that could be key to controlling evidence, I think there are some doubts that the CD8 CTLs will in fact clinically supply what is needed to control HIV. The studies we've so far may supply good indications that CD8s CTLs are key but clinical evidence is needed. I think the Remune studies may be important to supplying this answer because these studies will compare HAART+Remune vs HAART. Studies like this are needed in more advanced chronic infection to really prove that CD8 CTLs can make clinical improvements in more experienced people. For example, in people who've been on HAART for a number of years.