Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

Abstract

<jats:p>Cell-to-cell transmission of HIV has been proposed as a mechanism contributing to virus escape to the action of antiretrovirals and a mode of HIV persistence during antiretroviral therapy. Here, cocultures of infected HIV-1 cells with primary CD4<jats:sup>+</jats:sup>T cells or lymphoid cells were used to evaluate virus transmission and the effect of known antiretrovirals. Transfer of HIV antigen from infected to uninfected cells was resistant to the reverse transcriptase inhibitors (RTIs) zidovudine (AZT) and tenofovir, but was blocked by the attachment inhibitor IgGb12. However, quantitative measurement of viral DNA production demonstrated that all anti-HIV agents blocked virus replication with similar potency to cell-free virus infections. Cell-free and cell-associated infections were equally sensitive to inhibition of viral replication when HIV-1 long terminal repeat (LTR)-driven green fluorescent protein (GFP) expression in target cells was measured. However, detection of GFP by flow cytometry may incorrectly estimate the efficacy of antiretrovirals in cell-associated virus transmission, due to replication-independent Tat-mediated LTR transactivation as a consequence of cell-to-cell events that did not occur in short-term (48-h) cell-free virus infections. In conclusion, common markers of virus replication may not accurately correlate and measure infectivity or drug efficacy in cell-to-cell virus transmission. When accurately quantified, active drugs blocked proviral DNA and virus replication in cell-to-cell transmission, recapitulating the efficacy of antiretrovirals in cell-free virus infections and<jats:italic>in vivo</jats:italic>.</jats:p>

Relative contribution of free-virus and synaptic transmission to the spread of HIV-1 through target cell populations

“…Similarly, it is possible that multiple infection through synapses can saturate anti-viral drugs, such as reverse transcriptase inhibitors, which could contribute to ongoing viral replication during drug therapy [16]. How much this influences treatment responses is currently unclear [17], and depends on the relative importance of synaptic transmission, a first estimate of which has been provided here. Further discussion of the in vivo relevance is given in the electronic supplementary material.…”

Trans-infection but Not Infection from within Endosomal Compartments after Cell-to-cell HIV-1 Transfer to CD4+ T Cells

“…Our results reinforce the idea that endocytosed virus after cell-to-cell contacts may represent an itinerant virus reservoir able to induce the trans-infection of bystander T cells, but not leading to effective virus fusion or replication from within internal endosomal compartments. The contribution of this mechanism in the pathogenesis of HIV in vivo still needs to be completely clarified but should be taken into account when developing new antiviral strategies (36).…”

Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission

“…We demonstrated significant differences in the neutralization profiles of Env glycoproteins expressed in one chronic infection strain compared to three T/F HIV-1 strains. Most studies to date that have investigated cellassociated virus transmission have primarily focused on laboratory-adapted HIV-1 strains with few T/F isolates (10,12,74). Due to the recently appreciated importance of T/F viruses in HIV-1 transmission and pathogenesis, more focus has shifted toward studying T/F viral isolates and Env variants (75)(76)(77).…”