HIV-1 Antigen–specific and –nonspecific B Cell Responses Are Sensitive to Combination Antiretroviral Therapy

Abstract

We studied how combination antiviral therapy affects B cell abnormalities associated with HIV-1 infection, namely elevated circulating immunoglobulin (Ig)G antibody-secreting cell (ASC) frequencies and hypergammaglobulinemia. Within a few weeks of starting antiviral therapy, there is a marked decline in IgG-ASC frequency in both acutely and chronically infected people, whereas the hypergammaglobulinemia often present during chronic infection is more gradually resolved. These reductions are sustained while HIV-1 replication is suppressed. HIV-1 antigen–specific B cell responses are also affected by therapy, manifested by a rapid decline in circulating gp120-specific ASCs. Anti-gp120 titers slowly decrease in chronically infected individuals and usually fail to mature in acutely infected individuals who were promptly treated with antiretroviral therapy. Long-term nonprogressors have high titer antibody responses to HIV-1 antigens, but no detectable gp120-specific IgG-ASC, and normal (or subnormal) levels of total circulating IgG-ASC. Overall, we conclude that HIV-1 infection drives B cell hyperactivity, and that this polyclonal activation is rapidly responsive to decreases in viral replication caused by combination antiviral therapy.

Anti-human immunodeficiency virus type 1 humoral immune response and highly active antiretroviral treatment

“…Titers of "binding antibodies" (bAb = antibodies detectable through their in vitro binding to synthetic proteins or peptides) have been shown to decrease during successful HAART (Morris et al 2001, Bailey et al 2006. However, generation of specific anti-HIV antibodies in absence of detectable viremia has been described, indicative of retention of HIV antigen over long periods (Kim et al 2001, Popovic et al 2005) and restoration of normal B cell functions during HAART (Morris et al 1998, David et al 1999. Nevertheless, there are indications that the moment of HAART initiation defines the consequential restoration in the immune response (Mocroft et al 2003, Manzardo et al 2007, Chehimi et al 2007): the extent of immune response alterations caused in HIV infection will define restoration, but the quantitative immune stimulation induced by HIV will also be important for the extent of specific anti-HIV response detectable during or after successful antiretroviral therapy.…”

Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms

“…Among B cells, a large number of these defects have been associated with HIV-induced immune activation, as evidenced by hypergammaglobulinemia, increased expression of B cell activation markers, decreased responsiveness to B cell stimuli, and increased susceptibility to oncogenesis (1)(2)(3). Several studies have demonstrated that after reduction of HIV plasma viremia by antiretroviral therapy, B cell abnormalities subside, especially those thought to be directly or indirectly associated with virus-induced aberrant immune activation (4)(5)(6). We have demonstrated previously both in longitudinal and cross-sectional analyses that overrepresentation of a distinct B cell population, defined by reduced expression of CD21 and increased secretion of immunoglobulins (7), is likely to be responsible for several of the B cell defects that have been associated with ongoing HIV replication (8)(9)(10).…”

Antibody Detection and Kinetics of Antibody Production during Early Stages of Immunization with Hepatitis B Virus Vaccine

“…However, by the method used here the detection of anti-HBs in the lysates of purified B cells is considerably easier than their detection in cultured B cells or peripheral blood mononuclear cell (PBMC) supernatants, as reported by others (3,18,24). Intra-B-cell antibodies are not yet fully processed and so lack the correct glycosylation and are incompletely assembled (1,28).…”

“…The binding protein is later replaced by proper L chains (15). Both antibodies designated for secretion and membrane-bound antibodies are produced through similar pathways (4,18,20,30). If lymphocytes were disrupted at this point and antibodies were recovered, these B-cell-associated antibodies would therefore appear to be in different stages of assembly and maturity (8,14,27).…”