Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal
Sub-Saharan Africa accounts for almost 70 % of people living with HIV (PLWH) worldwide, with the greatest numbers centred in South Africa where 98 % of infections are caused by subtype C (HIV-1C). However, HIV-1 subtype B (HIV-1B), prevalent in Europe and North America, has been the focus of most cu...
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Elsevier
2024-12-01
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| Series: | Journal of Virus Eradication |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2055664024001900 |
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| author | Shreyal Maikoo Robert-Jan Palstra Krista L. Dong Tokameh Mahmoudi Thumbi Ndung'u Paradise Madlala |
| author_facet | Shreyal Maikoo Robert-Jan Palstra Krista L. Dong Tokameh Mahmoudi Thumbi Ndung'u Paradise Madlala |
| author_sort | Shreyal Maikoo |
| collection | DOAJ |
| description | Sub-Saharan Africa accounts for almost 70 % of people living with HIV (PLWH) worldwide, with the greatest numbers centred in South Africa where 98 % of infections are caused by subtype C (HIV-1C). However, HIV-1 subtype B (HIV-1B), prevalent in Europe and North America, has been the focus of most cure research and testing despite making up only 12 % of HIV-1 infections globally. Development of latency models for non-subtype B viruses is a necessary step to address this disproportionate focus. Furthermore, the impact of genetic variation between viral subtypes, specifically within the long terminal repeat (LTR) element of the viral transcriptional promoter on latency reversal, remains unclear. To address this scientific gap, we constructed a minimal genome retroviral vector expressing HIV-1C consensus transactivator of transcription protein (Tat) and green fluorescent protein (GFP) under the control of either HIV-1C consensus LTR (C731CC) or the transmitted/founder (T/F) LTRs derived from PLWH (CT/F731CC), produced corresponding LTR pseudotyped viruses using a vesicular stomatitis virus (VSV-G) pseudotyped Envelope vector and the pCMVΔR8.91 packaging vector containing HIV-1 accessory and rev genes. Viruses produced in this way were used to infect Jurkat E6 and primary CD4+ T cells in vitro. By enriching for latently infected cells, and treating them with different latency reversing agents, we developed an HIV-1C latency model that demonstrated that the HIV-1C consensus LTR has lower reactivation potential compared to its HIV-1B counterpart. Furthermore, HIV-1C T/F LTR pseudotyped proviral genetic variants exhibited a heterogenous reactivation response which was modulated by host cell (genetic) variation. Our data suggests that genetic variation both within and between HIV-1 subtypes influences latency reversal. Future studies should investigate the specific role of variation in host cellular environment on reactivation differences. |
| format | Article |
| id | doaj-art-9838ee6cccf14192bb6a4595553e6394 |
| institution | Kabale University |
| issn | 2055-6640 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Virus Eradication |
| spelling | doaj-art-9838ee6cccf14192bb6a4595553e63942025-01-27T04:21:50ZengElsevierJournal of Virus Eradication2055-66402024-12-01104100575Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversalShreyal Maikoo0Robert-Jan Palstra1Krista L. Dong2Tokameh Mahmoudi3Thumbi Ndung'u4Paradise Madlala5HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South AfricaDepartment of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, the Netherlands; Department of Pathology, Erasmus University Medical Center, the Netherlands; Department of Urology, Erasmus University Medical Center, the NetherlandsRagon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Massachusetts General Hospital, Infectious Disease Division, Boston, MA, USA; Harvard Medical School, Cambridge, MA, USADepartment of Biochemistry, Erasmus University Medical Center, PO Box 2040, 3000CA, Rotterdam, the Netherlands; Department of Pathology, Erasmus University Medical Center, the Netherlands; Department of Urology, Erasmus University Medical Center, the NetherlandsHIV Pathogenesis Programme, The Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA; Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa; Division of Infection and Immunity, University College London, London, United KingdomHIV Pathogenesis Programme, The Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Corresponding author. University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa.Sub-Saharan Africa accounts for almost 70 % of people living with HIV (PLWH) worldwide, with the greatest numbers centred in South Africa where 98 % of infections are caused by subtype C (HIV-1C). However, HIV-1 subtype B (HIV-1B), prevalent in Europe and North America, has been the focus of most cure research and testing despite making up only 12 % of HIV-1 infections globally. Development of latency models for non-subtype B viruses is a necessary step to address this disproportionate focus. Furthermore, the impact of genetic variation between viral subtypes, specifically within the long terminal repeat (LTR) element of the viral transcriptional promoter on latency reversal, remains unclear. To address this scientific gap, we constructed a minimal genome retroviral vector expressing HIV-1C consensus transactivator of transcription protein (Tat) and green fluorescent protein (GFP) under the control of either HIV-1C consensus LTR (C731CC) or the transmitted/founder (T/F) LTRs derived from PLWH (CT/F731CC), produced corresponding LTR pseudotyped viruses using a vesicular stomatitis virus (VSV-G) pseudotyped Envelope vector and the pCMVΔR8.91 packaging vector containing HIV-1 accessory and rev genes. Viruses produced in this way were used to infect Jurkat E6 and primary CD4+ T cells in vitro. By enriching for latently infected cells, and treating them with different latency reversing agents, we developed an HIV-1C latency model that demonstrated that the HIV-1C consensus LTR has lower reactivation potential compared to its HIV-1B counterpart. Furthermore, HIV-1C T/F LTR pseudotyped proviral genetic variants exhibited a heterogenous reactivation response which was modulated by host cell (genetic) variation. Our data suggests that genetic variation both within and between HIV-1 subtypes influences latency reversal. Future studies should investigate the specific role of variation in host cellular environment on reactivation differences.http://www.sciencedirect.com/science/article/pii/S2055664024001900Genetic variationHIV-1C latencyHIV-1 subtype CReactivationTransmitted founder (T/F) |
| spellingShingle | Shreyal Maikoo Robert-Jan Palstra Krista L. Dong Tokameh Mahmoudi Thumbi Ndung'u Paradise Madlala Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal Journal of Virus Eradication Genetic variation HIV-1C latency HIV-1 subtype C Reactivation Transmitted founder (T/F) |
| title | Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal |
| title_full | Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal |
| title_fullStr | Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal |
| title_full_unstemmed | Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal |
| title_short | Development of a latency model for HIV-1 subtype C and the impact of long terminal repeat element genetic variation on latency reversal |
| title_sort | development of a latency model for hiv 1 subtype c and the impact of long terminal repeat element genetic variation on latency reversal |
| topic | Genetic variation HIV-1C latency HIV-1 subtype C Reactivation Transmitted founder (T/F) |
| url | http://www.sciencedirect.com/science/article/pii/S2055664024001900 |
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