Memory Responses in Human Immunodeficiency Virus Type 1-Infected Individuals with Long-Term Viral Load Suppression Are Independent of CD4 Cell Nadir

Abstract

The persistence of memory responses in suppressive highly active antiretroviral therapy (HAART) has been an area of controversy. By using a previously described proliferation assay that augments specific responses, peripheral blood lymphocytes (PBL) from 61 human immunodeficiency virus type 1-seropositive individuals with CD4 counts of >300/mm 3 and suppressed viral burdens were studied for response to p24 antigen as a function of time of viral load suppression on HAART. In the majority of cases, proliferative responses could be measured in PBL from patients with plasma viral load suppression. No differences could be found in proliferative responses from PBL between individuals with a low and those with a high CD4 cell nadir. PBL that did not respond to either Casta antigen or p24 were found to have a higher percentage of naïve cells than did PBL that responded well to antigen. These data support the contention that, after long-term viral load suppression, PBL from infected individuals have memory cell populations that can respond to antigenic stimulation under inducible conditions.Highly active antiretroviral therapy (HAART) has significantly modified the interaction between host immunity and the virus. The response to HAART has been dramatic even in those individuals with low CD4 counts. The excitement associated with this immunologic recovery has been tempered by an inability to eradicate the infection and prevent disease progression in many cases. One area of interest is the role of an individual's CD4 cell nadir in predicting disease recovery or progression. It has been shown that individuals started on HAART with a low CD4 cell nadir do not recover CD4 cell levels to those of uninfected individuals (e.g., see reference 16). Furthermore, the CD4 cell nadir may negatively predict disease progression for individuals with comparable CD4 cell counts (12,18). Since the ability to respond to immunologic challenge is dependent on memory cells and the ability to develop these cell populations from an existing or replenished naïve cell pool, it is possible that peripheral blood lymphocytes (PBL) from individuals with recovering CD4 counts from low CD4 cell nadirs are not as responsive as PBL from those with higher nadirs. There have been many studies evaluating proliferative responses to human immunodeficiency virus (HIV) antigens after long periods on suppressive HAART, but the results have been equivocal (1,2,5,8,22,24,25,27). In an earlier study we demonstrated that memory cell proliferative responses to p24 antigen could be measured in a sensitive and specific manner when lipopolysaccharide (LPS) was used to drive T-cell proliferation through interactions with adherent monocytes (15). In the present study we use this assay to evaluate memory cell proliferative responses to p24 in PBL from HIV-infected individuals with suppressed viral loads (VLs) and CD4 counts greater than 300/mm 3 . The effect of duration of VL suppression and CD4 cell nadir on responsiveness to antigen is evaluated.