Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

Many attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1A preventative vaccine is urgently needed to curb the growing human immunodeficiency virus type 1 (HIV-1) epidemic and reduce the global economic burden of supplying lifelong antiretroviral therapies. The induction of antibodies (Abs) capable of neutralizing a broad range of viral strains is a major goal of HIV-1 vaccine research. Such broadly neutralizing Abs (BnAbs) have been isolated from HIV-1-infected individuals, and passive transfer of BnAbs to nonhuman primates has proven sufficient to prevent infection upon challenge with cell-free chimeric simianhuman immunodeficiency viruses (SHIV) (1-3). Despite the potential of BnAbs to prevent HIV-1 infection, a vaccine capable of eliciting BnAbs in HIV-1-uninfected individuals has not yet been designed. The lack of appropriate immunogens and the extensive somatic hypermutation within the variable regions of BnAbs are major impediments to their induction via vaccination (4). This inability to elicit BnAbs through immunization has spurred research interest into the potential of nonneutralizing effector functions of Abs to provide protection against HIV-1.Interest in the potential of the nonneutralizing effector functions of Abs has also been stimulated by the recent phase III human RV144 vaccine trial in Thailand, which provided evidence that nonneutralizing Ab-associated effector functions may be involved in Ab-conferred protection against HIV-1 infection (5, 6). Indeed, correlates of immunity analyses revealed that, in the absence of broadly neutralizing Abs, both high levels of IgG Abs to the V1V2 regions of the HIV-1 Env and low levels of plasma an-

Section: Discussionmentioning

confidence: 99%

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confidence: 93%

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confidence: 99%

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Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

Gooneratne

Richard

Lee

et al. 2015

“…Evidence demonstrating the efficiency of cell-to-cell HIV-1 transmission and the inability to abolish cell-associated virus (3,13,(16)(17)(18) emphasizes the need to determine which therapeutic or preventive agents neutralize cell-associated in addition to cell-free HIV-1. Viral inhibitors used as microbicides and antiretroviral therapy (ART) drugs have been developed to prevent HIV-1 transmission or to treat individuals infected with HIV-1 (19)(20)(21).…”

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confidence: 99%

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

Gombos

Kolodkin-Gal

Eslamizar

et al. 2015

Self Cite

To date, most therapeutic and vaccine candidates for human immunodeficiency virus type 1 (HIV-1) are evaluated preclinically for efficacy against cell-free viral challenges. However, cell-associated HIV-1 is suggested to be a major contributor to sexual transmission by mucosal routes. To determine if neutralizing antibodies or inhibitors block cell-free and cell-associated virus transmission of diverse HIV-1 strains with different efficiencies, we tested 12 different antibodies and five inhibitors against four green fluorescent protein (GFP)-labeled HIV-1 envelope (Env) variants from transmitted/founder (T/F) or chronic infection isolates. We evaluated antibody/inhibitor-mediated virus neutralization using either TZM-bl target cells, in which infectivity was determined by virus-driven luciferase expression, or A3R5 lymphoblastoid target cells, in which infectivity was evaluated by GFP expression. In both the TZM-bl and A3R5 assays, cell-free virus or infected CD4؉ lymphocytes were used as targets for neutralization. We further hypothesized that the combined use of specific neutralizing antibodies targeting HIV-1 Env would more effectively prevent cell-associated virus transmission than the use of individual antibodies. The tested antibody combinations included two gp120-directed antibodies, VRC01 and PG9, or VRC01 with the gp41-directed antibody 10E8. Our results demonstrated that cell-associated virus was less sensitive to neutralizing antibodies and inhibitors, particularly using the A3R5 neutralization assay, and the potencies of these neutralizing agents differed among Env variants. A combination of different neutralizing antibodies that target specific sites on gp120 led to a significant reduction in cell-associated virus transmission. These assays will help identify ideal combinations of broadly neutralizing antibodies to use for passive preventive antibody administration and further characterize targets for the most effective neutralizing antibodies/inhibitors. IMPORTANCEPrevention of the transmission of human immunodeficiency virus type 1 (HIV-1) remains a prominent goal of HIV research. The relative contribution of HIV-1 within an infected cell versus cell-free HIV-1 to virus transmission remains debated. It has been suggested that cell-associated virus is more efficient at transmitting HIV-1 and more difficult to neutralize than cell-free virus. Several broadly neutralizing antibodies and retroviral inhibitors are currently being studied as potential therapies against HIV-1 transmission. The present study demonstrates a decrease in neutralizing antibody and inhibitor efficiencies against cellassociated compared to cell-free HIV-1 transmission among different strains of HIV-1. We also observed a significant reduction in virus transmission using a combination of two different neutralizing antibodies that target specific sites on the outermost region of HIV-1, the virus envelope. Therefore, our findings support the use of antibody combinations against both cell-free and cell-associated virus in fu...

“…Most HIV studies have relied on the use of cell-free virus for infection due to convenience even though it is clear that cell-associated transmission is also important (37,38), with some reports indicating that infection via cell-free versus cell-associated routes might occur at different speeds and efficiencies (39). A recent report indicates that cell-to-cell transmission is required to trigger apoptosis of infected CD4 ϩ T cells (40).…”

Section: Discussionmentioning

confidence: 99%

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1

Quan

Han

et al. 2017

HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-tocell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.IMPORTANCE Specific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.KEYWORDS HIV-1, Env mutant, cell-associated viruses, cell dependence, reversion H IV-1 infection of cells can be efficiently established by free virus or directly via cell-cell contact, both involving the binding of the HIV gp120 protein to the cellular CD4 receptor and either the CCR5 or CXCR4 coreceptor (1-3). It has been reported that cell-to-cell transmission is more physiologically relevant and efficient although cell-free HIV may be used to initiate new infections in tissue culture (4-7).HIV-1 entry into target cells is believed to be a multistep and complex process initiated by the envelope protein gp120 binding to cell surface CD4, triggering conformational changes of gp120, followed by a second-step interaction between gp120 and either CXCR4 or CCR5, resulting in fusion between the viral envelope and the cellular plasma membrane (8). In addition to viral gp120 and other viral proteins, several host cell components, including intrinsic immune factors (9) and histocompatibility antigens, can influence HIV infectivity (10, 11). However, some viral factors can also counteract innate host defense mechanisms (12). It has also been reported that HIV can under some circumstances enter target cells via a CD4/coreceptor-independent mechanism (13-18), potentially broadening the spectrum of cells that HIV is able to infect.