Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Abstract

Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120͞gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 ؋ 10 3 to 6.3 ؋ 10 5 copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV1p17, -p24, and -gp120͞gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

“…Popovic et al previously demonstrated persistence of p17 but not viral RNA in lymph nodes of patients on cART who were virally suppressed (16), suggesting the presence of soluble p17 in these tissues. If so, the impact of p17 on B-cell growth is likely to persist.…”

“…Recent data indicate that the intrapatient diversity of amino acid sequences of the p17 protein is much higher than expected (15), thus suggesting that p17 variants (vp17s) potentially endowed with different biologic effects may spontaneously originate in HIV-1-infected cells. Considering that p17 may accumulate and persist within lymphoid tissues, even in patients treated with cART (16), the possibility that vp17s with lymphomagenic properties may be enriched in some HIV+ patients with possible predilection for lymphomas is a testable hypothesis. Here we report on the amino acid sequence associated with lymphomas and the structural impacts of some, which may result in biologic effects of potential pathogenic relevance for the development of HIV-NHL.…”

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

“…Although seroreversion appears to be rare even after years of successful antiviral therapy, the gradual decrease of specific anti-HIV-1 antibodies is a well known occurrence in HAART patients (Béniguel et al 2004, Amor et al 2006, Cornelissen et al 2006. Several hypotheses have been raised to explain the maintenance of a humoral anti-HIV-1 immune response after years of apparent absence of HIV-1 antigenic stimulation, including maintenance of HIV-1 antigens associated to follicular dendritic cells in patients with undetectable viremia (Popovic et al 2005).…”

“…It is also thought that the low level of HIV replication during successful HAART may prevent induction of a high titer antibody response (Popovic et al 2005, Bailey et al 2006, and, although sporadic cases of a high autologous neutralizing antibody (NAb) have been reported, the NAb response during HAART is poorly understood , Dreyer et al 1999. 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.…”

“…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.…”