Antigen-Presenting Cell Modulation Induces a Memory Response to p24 in Peripheral Blood Leukocytes from Human Immunodeficiency Virus-Infected Individuals

Abstract

The accurate determination of human immunodeficiency virus type 1 (HIV-1)-specific proliferative responses is critically important when evaluating immune recovery after highly active antiretroviral therapy. Using a new assay to enhance proliferative responses to recall and HIV antigen, we addressed the questions of whether viral load affects cellular immunity and whether long-term viral load suppression results in loss of antigen-specific responder cells. This assay is based on the fact that lipopolysaccharide (LPS) can augment proliferative responses to antigen after monocyte adherence to a tissue culture plate. Twenty-six HIV-1-infected individuals donated peripheral blood leukocytes (PBL). Proliferation assays against p24, using LPS and cell adherence, were performed on all samples. Medical record abstraction provided information on CD4 cell nadir and time of viral load suppression. PBL from HIV-1-infected individuals with a viral load of <200 copies/ml had a significant proliferative response and a stimulation index of >5 to p24 (12 of 15) compared to those with a viral burden (2 of 11), using the LPS-adherence assay. Proliferative responses to p24 could be found in PBL from virally suppressed donors independent of the CD4 cell nadirs and in the majority of the donors who were virally suppressed for >10 months (7 of 10). The data presented here demonstrate that LPS and monocyte adherence provide a sensitive and specific way to boost proliferative responses to recall and HIV antigens.The impact of highly active antiretroviral therapy (HAART) on immune reconstitution has been clearly demonstrated in those individuals with advanced disease. When a human immunodeficiency virus type 1 (HIV-1)-infected individual with AIDS is aggressively treated with antiretroviral therapy, the viral load is suppressed and the CD4 count frequently is elevated above 200 cells/mm 3 . This permits discontinuation of prophylaxis for opportunistic infections and, in the long term, results in an enhanced period of survival and a decrease in disease progression. However, there are still numerous questions regarding the level of cellular immunity and which factors affect this parameter.Although it is known that defects in the immune repertoire exist early in infection (31, 36) and progress as the disease advances (12), the ability to reconstitute immunity most likely depends on numerous host factors and comorbid conditions. As a further confounding variable, the role of the viral load as an independent predictor of disease progression for CD4 counts greater than 350 cells/mm 3 has been difficult to ascertain (22), even in light of the in vitro data suggesting immunesuppressive effects of the virus on proliferation to recall and HIV-1 antigens (28,30,37). Incomplete reconstitution in some individuals is suggested by the fact that the incidence of malignancy continues to be high in individuals infected with and treated for their HIV-1 disease (9,27).With the ongoing efforts in HIV vaccine research, the ability to identify individuals with ...

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

“…Therefore, it is important to understand whether HIV-infected individuals have persistent long-term memory responses to recall antigen and to measure them accurately. In an earlier study we described an assay that used LPS and monocyte adherence to augment specific proliferative responses to p24 (15). In the study described here we use this assay to evaluate proliferative responses to p24 in a HAART-suppressed cohort of infected individuals with CD4 counts greater than 300 cells/ mm 3 .…”

“…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 .…”

Impact of Immune Plasticity on Development of Cellular Memory Responses to Human Immunodeficiency Virus Type 1

“…Results from proliferation experiments have been mixed in regard to demonstrating PBL memory responses to HIV antigens from suppressed donors (2,5,9,13,47,48,50,57). The differences between these findings may be one of assay sensitivity rather than one of an inability to respond to antigen (28). A number of studies have evaluated cytotoxic T-lymphocyte (CTL) specificity in PBLs from individuals during structured interruption of suppressive HAART in HIV-1-infected individuals (4,42).…”