Matrix Fibronectin Increases HIV Stability and Infectivity

Abstract

HIV particles are detected extracellularly in lymphoid tissues, a major reservoir of the virus. We previously reported that a polymerized form of fibronectin (FN), superfibronectin (sFN), as well as a fragment of FN, III1-C, enhanced infection of primary CD4+ T cells by HIV-1IIIB. We now show that sFN enhances infection of primary CD4+ T cells by both R5 and X4 strains of HIV-1. Using HIV pseudotyped with different envelope glycoproteins (gp120) and HOS cells transfected with various chemokine receptors alone or in combination with the CD4 molecule, we show that sFN-mediated enhancement requires the CD4 receptor and does not alter the specificity of gp120 for different chemokine receptors. Because the III1-C fragment also resulted in enhancement, we asked whether proteolysis of FN generated fragments capable of enhancing HIV infection. We found that progressive proteolysis of FN by chymotrypsin correlates with an enhancement of HIV infection in both primary CD4+ T cells and the IG5 reporter cell line. Furthermore, incubation of HIV with sFN significantly prolonged infectivity at 37°C compared with dimeric FN or BSA. In conclusion, these results indicate that polymerized (matrix) or degraded (inflammation-associated), but not dimeric (plasma), FN are capable of enhancing infection by HIV-1, independent of the coreceptor specificity of the strains. Moreover, virions bound to matrix FN maintain infectivity for longer periods of time than do virions in suspension. This study suggests that matrix proteins and their conformational status may play a role in the pathogenesis of HIV.

Impact of Fibronectin Fragments on the Transendothelial Migration of HIV-Infected Leukocytes and the Development of Subendothelial Foci of Infectious Leukocytes

“…Recent reports suggest that diverse forms of matrix FN can stabilize virions of HIV-1 on the surface of infected cells and help facilitate the transmission of infectious virus (24,25). We have also found that addition of FNf to cultures of in vitro infected MNLs stimulated with IL-2 increases by 2-to 4-fold the quantity of p24 generated over the next 3 days (data not shown).…”

“…Recent studies have called attention to the possibility that proteolytic fragments or polymers of FN may be among the factors that influence leukocyte behavior in inflamed tissues (23)(24)(25). Certain FN fragments can stabilize and enhance the infectivity of cell-associated virus (24,25); other FN subunits can activate monocytes and cause them to release TNF-␣ through a protein kinase C-dependent signaling pathway (26 -30).…”

“…Recent studies have called attention to the possibility that proteolytic fragments or polymers of FN may be among the factors that influence leukocyte behavior in inflamed tissues (23)(24)(25). Certain FN fragments can stabilize and enhance the infectivity of cell-associated virus (24,25); other FN subunits can activate monocytes and cause them to release TNF-␣ through a protein kinase C-dependent signaling pathway (26 -30). Because the release of monocyte intracytoplasmic TNF-␣ drives lymphocyte transendothelial migration (18,31), we investigated the abilities of FN fragments to stimulate lymphocyte transendothelial migration and create subendothelial foci of infected cells that could disseminate virus-infected cells to distant sites.…”

HIV-Infected Lymphocytes Regulate Fibronectin Synthesis by TGFβ1 Secretion

“…We previously reported that HIV virions adhered efficiently to superfibronectin, an in vitro model for matrix fibronectin (3). Superfibronectin-bound virions had enhanced infectivity and maintained their infectivity significantly longer than unbound virions (2). Additionally, proteolytic fragments of fibronectin containing the III1-C region also enhanced HIV infection.…”

“…We previously showed that fibronectin deposition was increased in lymph nodes during HIV infection but did not find a difference in fibronectin synthesis by HIV-infected lymphocytes (2). Therefore, we hypothesized that interactions of HIV-infected lymphocytes with fibroblasts would result in increased fibronectin synthesis by fibroblasts.…”