Identification of Human Endogenous Retrovirus-Specific T Cell Responses in Vertically HIV-1-Infected Subjects

Tandon, Ravi; SenGupta, Devi; Ndhlovu, Lishomwa C.; Vieira, Raphaella G. S.; Jones, R. Brad; York, Vanessa A.; Vieira, Vinícius; Sharp, Elizabeth R.; Wiznia, Andrew; Ostrowski, Mario; Rosenberg, Michael; Nixon, Douglas F.

doi:10.1128/jvi.05418-11

Cited by 31 publications

(30 citation statements)

References 27 publications

(26 reference statements)

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“…Early support for the induction of HERV antigen expression in HIV-1-infected subjects was provided by our observation that T cell responses to a variety of HERV-derived peptides are detectable in HIV-1-infected subjects but not in uninfected controls (25,26). Supporting the in vivo relevance of these responses, we observed that strong HERV-specific T cell responses were associated with control of HIV-1 replication (25,27).…”

Section: Figuresupporting

confidence: 60%

“…HERV-K(HML-2)-Env-and Gag-specific T cell responses detectable by 15-mer peptides are rare (29). Hence, to generate additional HERV-K(HML-2)-specific T cell clones we screened subjects using optimal HERV-K(HML-2) determinants identified in our previous studies (25)(26)(27). We generated a CD8 + T cell clone specific for the HERV-K(HML-2)-Pol epitope FAFTI-PAI from an individual with early (<1 year) HIV-1 infection and determined this response to be HLA-B*51 restricted.…”

Section: Cross-reactive Hiv-1/herv-k(hml-2)-specific T Cells Exist Anmentioning

confidence: 99%

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HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

Jones¹,

Garrison²,

Mujib³

et al. 2012

J. Clin. Invest.

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Section: Figuresupporting

confidence: 60%

Section: Cross-reactive Hiv-1/herv-k(hml-2)-specific T Cells Exist Anmentioning

confidence: 99%

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

Jones¹,

Garrison²,

Mujib³

et al. 2012

J. Clin. Invest.

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“…The consequence of this increased expression of transmissible HK2 viruses, for both HIV-1-infected cells and the HIV-1-infected individual, remains to be elucidated. However, it is important to note that expression of HK2 epitopes, and perhaps transmissible HK2 viruses, on HIV-1-infected cells render these cells susceptible to lysis by immune T cells and antibody responses directed against HK2, creating a tool that conceivably could be used to eradicate HIV-1 infection (93)(94)(95).…”

Section: Discussionmentioning

confidence: 99%

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Contreras-Galindo

Kaplan

Dube

et al. 2015

J Virol

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Human endogenous retroviruses (HERV) make up 8% of the human genome. While the youngest of these retroviruses, HERV-K(HML-2), termed HK2, is able to code for all viral proteins and produce virus-like particles, it is not known if these virus particles package and transmit HK2-related sequences. Here, we analyzed the capacity of HK2 for packaging and transmitting HK2 sequences. We created an HK2 probe, termed Bogota, which can be packaged into HK2 viruses, and transfected it into cells that make HK2 particles. Supernatants of the transfected cells, which contained HK2 viral particles, then were added to target cells, and the transmissibility of the HK2 Bogota reporter was tracked by G418 resistance. Our studies revealed that contemporary HK2 virions produced by some teratocarcinoma and breast cancer cell lines, as well as by peripheral blood lymphocytes from lymphoma patients, can package HK2 Bogota probes, and these viruses transmitted these probes to other cells. After transmission, HK2 Bogota transcripts undergo reverse transcription, a step impaired by antiretroviral agents or by introduction of mutations into the probe sequences required for reverse transcription. HK2 viruses were more efficiently transmitted in the presence of HK2 Rec or HIV-1 Tat and Vif. Transmitted Bogota probes formed episomes but did not integrate into the cellular genome. Resistance to integration might explain the relatively low number of HK2 insertions that were acquired during the last 25 million years of evolution. Whether transient transmission of modern HK2 sequences, which encode two putative oncoproteins, can lead to disease remains to be studied. IMPORTANCERetroviruses invaded the genome of human ancestors over the course of millions of years, yet these viruses generally have been inactivated during evolution, with only remnants of these infectious sequences remaining in the human genome. One of these viruses, termed HK2, still is capable of producing virus particles, although these particles have been regarded as being noninfectious. Using a genetic probe derived from HK2, we have discovered that HK2 viruses produced in modern humans can package HK2 sequences and transmit them to various other cells. Furthermore, the genetic sequences packaged in HK2 undergo reverse transcription. The transmitted probe circularized in the cell and failed to integrate into the cellular genome. These findings suggest that modern HK2 viruses can package viral RNA and transmit it to other cells. Contrary to previous views, we provide evidence of an extracellular viral phase of modern HK2 viruses. We have no evidence of sustained, spreading infection.A ctively replicating retroviruses infected the germ line multiple times over the millions of years of human evolution. These sequences were transmitted vertically in a Mendelian fashion to the next generation; therefore, they became a stable part of the inherited genetic material. Relics of these retroviral infections presently make up approximately 8% of the modern human genome. These retro...

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“…Several groups have detected antibody responses to HERV-K in a majority of HIV-1-positive patients but not in uninfected donors (41,54). Similarly, T cell responses to HERV-K were observed in HIV-1-infected patients but not in healthy donors (19,49,51). Furthermore, upregulation of HERV-K RNA was detected (14-17, 19, 40) in plasma samples of HIV-1-infected individuals, in HIV-1-infected T cells (17,38), and in HIV-1 Tat-transfected T cells (23).…”

mentioning

confidence: 99%

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Monde

Contreras-Galindo

Kaplan

et al. 2012

J Virol

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Human endogenous retroviruses (HERVs), which are remnants of ancestral retroviruses integrated into the human genome, are defective in viral replication. Because activation of HERV-K and coexpression of this virus with HIV-1 have been observed during HIV-1 infection, it is conceivable that HERV-K could affect HIV-1 replication, either by competition or by cooperation, in cells expressing both viruses. In this study, we found that the release efficiency of HIV-1 Gag was 3-fold reduced upon overexpression of HERV-K CON Gag. In addition, we observed that in cells expressing Gag proteins of both viruses, HERV-K CON Gag colocalized with HIV-1 Gag at the plasma membrane. Furthermore, HERV-K CON Gag was found to coassemble with HIV-1 Gag, as demonstrated by (i) processing of HERV-K CON Gag by HIV-1 protease in virions, (ii) coimmunoprecipitation of virion-associated HERV-K CON Gag with HIV-1 Gag, and (iii) rescue of a late-domain-defective HERV-K CON Gag by wild-type (WT) HIV-1 Gag. Myristylation-deficient HERV-K CON Gag localized to nuclei, suggesting cryptic nuclear trafficking of HERV-K Gag. Notably, unlike WT HERV-K CON Gag, HIV-1 Gag failed to rescue myristylation-deficient HERV-K CON Gag to the plasma membrane. Efficient colocalization and coassembly of HIV-1 Gag and HERV-K Gag also required nucleocapsid (NC). These results provide evidence that HIV-1 Gag heteromultimerizes with HERV-K Gag at the plasma membrane, presumably through NC-RNA interaction. Intriguingly, HERV-K Gag overexpression reduced not only HIV-1 release efficiency but also HIV-1 infectivity in a myristylation- and NC-dependent manner. Altogether, these results indicate that Gag proteins of endogenous retroviruses can coassemble with HIV-1 Gag and modulate the late phase of HIV-1 replication.

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Identification of Human Endogenous Retrovirus-Specific T Cell Responses in Vertically HIV-1-Infected Subjects

Cited by 31 publications

References 27 publications

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

Human Endogenous Retrovirus Type K (HERV-K) Particles Package and Transmit HERV-K–Related Sequences

Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

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