African Green Monkey TRIM5α Restriction in Simian Immunodeficiency Virus-Specific Rhesus Macaque Effector CD4 T Cells Enhances Their Survival and Antiviral Function

Abstract

The expression of xenogeneic TRIM5␣ proteins can restrict infection in various retrovirusT he TRIM5␣ cellular protein is a well-studied resistance factor (1) that is a major contributor to the inability of human immunodeficiency virus type 1 (HIV-1) to replicate in Old World monkey CD4 T cells, especially those from rhesus macaque (2-6). While endogenous TRIM5␣ does not restrict permissive virus-cell pairings, expression of xenogeneic TRIM5␣ can make cells resistant to infection (7-11). Experiments with xenogeneic expression of TRIM5␣ have revealed a somewhat complicated pattern of restriction in a variety of virus-host pairings (5,(7)(8)(9)(11)(12)(13)(14).Cytoplasmic TRIM5␣ restricts infection rapidly after viral entry (15), disrupting reverse transcription (2-5, 16, 17) as well as later stages of the infection process (16,17). During restriction, TRIM5␣ binds the retroviral capsid core, a capsid protein-coated structure which contains all of the viral molecules required for infection: the RNA genome, reverse transcriptase, and integrase. While the exact mechanism of restriction is not completely understood, two nonexclusive models posit that restricting TRIM5␣ binds the capsid core by forming a cage-like structure (18) that either causes the core to prematurely uncoat (16,(19)(20)(21), thereby interfering with reverse transcription, or engages the ubiquitin proteasome pathway through its ubiquitin ligase activity, causing the destruction of the caged core complex (10,17,(22)(23)(24). Because TRIM5␣ binds cooperatively to the capsid core and its cytoplasmic concentration is limiting, restriction is saturable: increasing amounts of viral cores entering the cell from high multiplicities of infection (MOI) titrate out cytoplasmic TRIM5␣, eliminating restriction (18,(25)(26)(27)(28).Conceptually, xenogeneic expression of rhesus macaque TRIM5␣ (rhTRIM5␣) by gene transfer is an approach to protect primary human CD4 T cells from HIV-1 in vivo (29-32). However, in vitro experiments have found that, while rhTRIM5␣-transduced cells protected human CD4 T cells in monoculture,

CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

“…One obstacle to this approach is the relatively low frequency of naturally occurring antiviral CD8 T cells, which require extensive expansion in culture to generate sufficient numbers of cells for infusion with its attendant poor persistence of adoptively transferred cells in lymphoid tissues (47,48). To overcome this limitation, we have developed an approach for transferring TCRs isolated from highly effective virus-suppressing T-cell clones by retroviral transduction (51)(52)(53). Large-scale transductions with these vectors can rapidly transfer well-characterized, functional antiviral TCR specificities into large numbers of T cells, thereby generating large and effective CD8 T-cell responses for adoptive transfer experiments (43,51,53).…”

“…To overcome this limitation, we have developed an approach for transferring TCRs isolated from highly effective virus-suppressing T-cell clones by retroviral transduction (51)(52)(53). Large-scale transductions with these vectors can rapidly transfer well-characterized, functional antiviral TCR specificities into large numbers of T cells, thereby generating large and effective CD8 T-cell responses for adoptive transfer experiments (43,51,53). Recently, we observed an antiviral effect by infusing engineered SIV-specific T cells in conjunction with SIV inoculation, manifested in a reduction of the number of transmitted/founder viruses in an acute infection model (43).…”

A novel SIV gag-specific CD4+T-cell clone suppresses SIVmac239 replication in CD4+T cells revealing the interplay between antiviral effector cells and their infected targets

“…Therefore, infection of the CD4 + effectors themselves can interfere with their ability to suppress virus spread due to both viral-induced cytopathogenic effects and fratricide of infected effector cells by their fellow effector T cells (Jain et al, 2015). Because this could reduce their overall effectiveness, we examined the infection status of the CD4 + effectors in the co-culture.…”

“…One striking difference between the two clones is the reduced levels of infected Gag68 cells compared to those in the Gag6 samples, highlighting the importance of CD4 + effectors reducing their own infection with its associated cytopathogenicity for efficient virus suppression in the targets (Jain et al, 2015). Similarly, the reduced Gag68 suppression in the 1:1 effector-to-target co-culture compared to its 10:1 counterpart was accompanied by an extensive amount of effector infection versus the 10:1 Gag68 co-culture.…”

“…Because one important difference between CD8 + and CD4 + effectors is that the CD4 + T-cell effectors are also targets of AIDS viruses themselves (Brenchley et al, 2006; Douek et al, 2001; Jain et al, 2015), we also examined the correlation between antiviral function and effector infection. Our results show that SIV Gag-specific CD4 + T cells can act as effectors, producing MHC class II (MHC-II)-restricted antigen-induced polyfunctional effector responses and direct suppression of SIV replication in both the CD4 + T-cell targets as well as themselves.…”