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AIDS/HIVs

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Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease
Carolina Caro-Vegas, … , Dirk P. Dittmer, Nader Kim El-Mallawany
Carolina Caro-Vegas, … , Dirk P. Dittmer, Nader Kim El-Mallawany
Published November 22, 2023
Citation Information: JCI Insight. 2023;8(22):e167854. https://doi.org/10.1172/jci.insight.167854.
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Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease

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Abstract

BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

Authors

Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L. McAtee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C. Peckham-Gregory, Razia Moorad, Carrie L. Kovarik, Liane R. Campbell, Parth S. Mehta, Peter N. Kazembe, Carl E. Allen, Michael E. Scheurer, Nmazuo W. Ozuah, Dirk P. Dittmer, Nader Kim El-Mallawany

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The latency reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific CD8+ T-cells
Dennis C. Copertino, Jr, … , Alberto Bosque, R. Brad Jones
Dennis C. Copertino, Jr, … , Alberto Bosque, R. Brad Jones
Published August 15, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.169028.
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The latency reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific CD8+ T-cells

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Abstract

IL-15 is under clinical investigation towards the goal of curing HIV infection, due to its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK function, by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV-specific cytotoxic T-cell responses. We show that ex vivo IL-15+HODHBt treatment markedly enhances HIV-specific granzyme B-releasing T-cell responses in PBMCs from ARV-suppressed donors. We also observed upregulation of antigen processing and presentation in CD4+ T-cells, and increased surface MHC-I. In ex vivo PBMCs, IL-15+HODHBt was sufficient to reduce intact proviruses in 1 of 3 ARV-suppressed donors. Our findings reveal the potential for 2nd-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.

Authors

Dennis C. Copertino, Jr, Carissa S. Holmberg, Jared Weiler, Adam R. Ward, J. Natalie Howard, Callie Levinger, Alina P.S. Pang, Michael J. Corley, Friederike Dündar, Paul Zumbo, Doron Betel, Rajesh T. Gandhi, Deborah K. McMahon, Ronald J. Bosch, Noemi Linden, Bernard J. Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, Colin Kovacs, Erica Benko, Alberto Bosque, R. Brad Jones

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T cell activation is insufficient to drive SIV disease progression
Cristian Apetrei, … , Ruy M. Ribeiro, Ivona Pandrea
Cristian Apetrei, … , Ruy M. Ribeiro, Ivona Pandrea
Published July 24, 2023
Citation Information: JCI Insight. 2023;8(14):e161111. https://doi.org/10.1172/jci.insight.161111.
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T cell activation is insufficient to drive SIV disease progression

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Abstract

Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.

Authors

Cristian Apetrei, Thaidra Gaufin, Egidio Brocca-Cofano, Ranjit Sivanandham, Paola Sette, Tianyu He, Sindhuja Sivanandham, Natalie Martinez Sosa, Kathryn J. Martin, Kevin D. Raehtz, Adam J. Kleinman, Audrey Valentine, Noah Krampe, Rajeev Gautam, Andrew A. Lackner, Alan L. Landay, Ruy M. Ribeiro, Ivona Pandrea

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Early ART reduces viral seeding and innate immunity in liver and lungs of SIV-infected macaques
Julien A. Clain, … , Ouafa Zghidi-Abouzid, Jérôme Estaquier
Julien A. Clain, … , Ouafa Zghidi-Abouzid, Jérôme Estaquier
Published July 24, 2023
Citation Information: JCI Insight. 2023;8(14):e167856. https://doi.org/10.1172/jci.insight.167856.
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Early ART reduces viral seeding and innate immunity in liver and lungs of SIV-infected macaques

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Abstract

Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy–treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR+CD11b+CD14+CD16+) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206+ and LYVE+). Sorting of myeloid cell subsets demonstrated that CD14+CD206–, CD14+CD206+, and CD14–CD206+ cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206+HLA-DR+CD11b+ cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.

Authors

Julien A. Clain, Henintsoa Rabezanahary, Gina Racine, Steven Boutrais, Calaiselvy Soundaramourty, Charles Joly Beauparlant, Mohammad-Ali Jenabian, Arnaud Droit, Petronela Ancuta, Ouafa Zghidi-Abouzid, Jérôme Estaquier

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Distinct mucosal and systemic immunological characteristics in transgender women potentially relating to HIV acquisition
Alexandra Schuetz, … , Lishomwa C. Ndhlovu, Sandhya Vasan
Alexandra Schuetz, … , Lishomwa C. Ndhlovu, Sandhya Vasan
Published July 11, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.169272.
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Distinct mucosal and systemic immunological characteristics in transgender women potentially relating to HIV acquisition

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Abstract

Transgender women (TGW) are disproportionally affected by HIV infection, with a global estimated prevalence of 19.9%, often attributed to behavioral risk factors, with less known about biological factors. We evaluated potential biological risk factors for HIV acquisition in TGW at the sites of viral entry by assessing immune parameters of neovaginal surface and gut mucosa. The neovagina in TGW, compared to the vagina in CW, shows distinct cell composition and may pose a more inflammatory environment, evidenced by increased CD4+ T cell activation and higher levels of soluble markers of inflammation (CRP, sCD30). Increased inflammation may be driven by microbiome composition, showing a greater abundance of Prevotella and a higher Shannon diversity. In addition, we have observed higher frequency of CD4+CCR5+ target cells and decreased DNA methylation of the CCR5 gene in the gut mucosa of TGW compared to CW and MSM which was inversely correlated with testosterone levels. The rectal microbiome composition in TGW appears to favor a proinflammatory milieu as well as mucosal barrier disruption. Thus, it is possible that increased inflammation and higher frequencies of CCR5-expressing target cells at sites of mucosal viral entry may contribute to increased risk of HIV acquisition in TGW, with further validation in larger studies warranted.

Authors

Alexandra Schuetz, Michael Corley, Carlo Sacdalan, Yuwadee Phuang-Ngern, Thitiyanun Nakpor, Tanyaporn Wansom, Philip K. Ehrenberg, Somchai Sriplienchan, Rasmi Thomas, Nisakorn Ratnaratorn, Suchada Sukhumvittaya, Nipattra Tragonlugsana, Bonnie M. Slike, Siriwat Akapirat, Suteeraporn Pinyakorn, Rungsun Rerknimitr, Alina P.S. Pang, Eugène Kroon, Nipat Teeratakulpisan, Shelly J. Krebs, Nittaya Phanuphak, Lishomwa C. Ndhlovu, Sandhya Vasan

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The TLR7-IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection
Liseth Carmona-Perez, … , Julien van Grevenynghe, Simona Stager
Liseth Carmona-Perez, … , Julien van Grevenynghe, Simona Stager
Published May 25, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.167329.
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The TLR7-IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection

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Abstract

HIV-1 infection is characterized by a strong inflammatory environment, tissue disruption, and a progressive decline in CD4+ T cell count. Despite treatment with antiretroviral therapy (ART), the majority of persons living with HIV (PLWH) maintain residual levels of inflammation, low degree of immune activation, and higher sensitivity to cell death in their memory CD4+ T-cell compartment. To date, the mechanisms responsible for this high sensitivity remain elusive. We have identified the transcription factor IRF-5 to be involved in impairing the maintenance of murine CD4+ T cells in a chronic inflammatory environment. Here, we investigate whether IRF-5 also contributes to memory CD4+ T cell loss during HIV-1 infection. We show that TLR7 and IRF-5 were upregulated in memory CD4+ T cells from PLWH, when compared with naturally protected elite controllers and HIVfree participants. TLR7 was upstream of IRF-5, promoting Caspase 8 expression in CD4+ T cells from ART HIV-1+ but not from HIVfree participants. Moreover, IRF-5 and TLR7 expression inversely correlated with CD4+ T cell counts in primary HIV infection. Interestingly, the TLR7-IRF-5 axis acted synergistically with the Fas/FasL pathway, suggesting that TLR7 and IRF-5 expression in ART HIV-1+ memory CD4+ T cells represents an imprint that predisposes cells to Fas-mediated apoptosis. This predisposition could be blocked using IRF-5 inhibitory peptides. Thus, we propose IRF-5 blockade as a possible therapy to prevent memory CD4+ T cell loss in PLWH.

Authors

Liseth Carmona-Perez, Xavier Dagenais-Lussier, Linh Thuy Mai, Tanja Stögerer, Sharada Swaminathan, Stephane Isnard, Matthew R. Rice, Betsy J. Barnes, Jean Pierre Routy, Julien van Grevenynghe, Simona Stager

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ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone
Margaret C. Costanzo, … , the RV306, RV328 study groups
Margaret C. Costanzo, … , the RV306, RV328 study groups
Published May 8, 2023
Citation Information: JCI Insight. 2023;8(9):e167664. https://doi.org/10.1172/jci.insight.167664.
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ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone

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Abstract

The RV144 phase III vaccine trial demonstrated that ALVAC-HIV and AIDSVAX B/E administration over 6 months resulted in 31% efficacy in preventing HIV acquisition, while administration of AIDSVAX B/E alone in both VAX003 and VAX004 studies failed to show efficacy. In this study, we aimed to understand the impact of ALVAC-HIV on the development of cellular, humoral, and functional immune responses compared to the administration of AIDSVAX B/E alone. ALVAC-HIV in combination with 3 doses of AIDSVAX B/E significantly increased CD4+ HIV-specific T cell responses, polyfunctionality, and proliferation compared with 3 doses of AIDSVAX B/E alone. Additionally, Env-specific plasmablasts and A244-specific memory B cells were identified with a significantly higher magnitude in the group that received ALVAC-HIV. Subsequently, data revealed increased magnitude of plasma IgG binding to and avidity for HIV Env in participants who received ALVAC-HIV compared with 3 doses of AIDSVAX B/E alone. Lastly, levels of the Fc-mediated effector functions antibody-dependent cellular cytotoxicity, NK cell activation, and trogocytosis were significantly increased in participants who received ALVAC-HIV compared with those receiving AIDSVAX B/E alone. Taken together, these results suggest that ALVAC-HIV plays an essential role in developing cellular and humoral immune responses to protein-boosted regimens relative to protein alone.

Authors

Margaret C. Costanzo, Dominic Paquin-Proulx, Alexandra Schuetz, Siriwat Akapirat, Zhanna Shubin, Dohoon Kim, Lindsay Wieczorek, Victoria R. Polonis, Hung V. Trinh, Mangala Rao, Hanna Anenia, Michael D. Barrera, Jacob Boeckelman, Barbara Nails, Pallavi Thapa, Michelle Zemil, Carlo Sacdalan, Eugene Kroon, Boot Kaewboon, Somporn Tipsuk, Surat Jongrakthaitae, Sanjay Gurunathan, Faruk Sinangil, Jerome H. Kim, Merlin L. Robb, Julie A. Ake, Robert J. O’Connell, Punnee Pitisutthithum, Sorachai Nitayaphan, Suwat Chariyalertsak, Michael A. Eller, Nittaya Phanuphak, Sandhya Vasan, the RV306, RV328 study groups

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Multi-ancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH
Candelaria Vergara, … , Eileen P. Scully, Paul J. McLaren
Candelaria Vergara, … , Eileen P. Scully, Paul J. McLaren
Published April 25, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.170068.
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Multi-ancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH

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Abstract

Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower setpoint viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex stratified genome-wide association study using data from the International Collaboration for the Genomics of HIV. Although it is the largest collection of genomic data in HIV, this multi-ethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males, and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100 (Pvalue=8.36x10-07), PCP2 (Pvalue=8.81x10-07), XAB2 (Pvalue=1.32x10-6) and STXBP2 (Pvalue=1.65x10-4) only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268,Pvalue=1.93x10-08) and PSORS1C2 (rs1265159, Pvalue=3.26x10-08) and on HIV control in SUB1 (rs687659, Pvalue=1.02×10-08), AL158151.3, PTPA and IER5L (rs4387067, Pvalue=2.07×10-09). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.

Authors

Candelaria Vergara, Jeffrey F. Tuff, International Collaboration for the Genomics of HIV, Jacques Fellay, Priya Duggal, Eileen P. Scully, Paul J. McLaren

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High-throughput proteomic analysis reveals systemic dysregulation in virally suppressed people living with HIV
Nadira Vadaq, … , André J.A.M. van der Ven, Vasiliki Matzaraki
Nadira Vadaq, … , André J.A.M. van der Ven, Vasiliki Matzaraki
Published April 20, 2023
Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.166166.
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High-throughput proteomic analysis reveals systemic dysregulation in virally suppressed people living with HIV

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Abstract

BACKGROUND. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV. METHOD. Proximity extension assay technology was utilized to measure 1472 plasma proteins. Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for the development of CVD during a 5-year follow-up. RESULTS. PLHIV on ART displayed systemic dysregulation of protein concentrations compared to HCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune- and lipid metabolism-related pathways. Furthermore, we observed that DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD in 5-year follow-up. CONCLUSIONS. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. TRIAL REGISTRATION. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835). FUNDING. The 200HIV and 2000HIV studies are supported by the AIDS-fonds (#P-29001, Netherlands) and a ViiV healthcare grant (A18-1052), respectively; The ViiV healthcare grant was awarded to A.V., M.G.N., L.A.B.J., and Q.d.M; The Spinoza Prize (NWO SPI94-212) and ERC Advanced grant (no. 833247) were awarded to M.G.N; The Indonesia Endowment Fund for Education (LPDP) given by the Ministry of Finance of the Republic of Indonesia was awarded to N.V.

Authors

Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje C.P. Jacobs-Cleophas, Lisa Van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki

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Cannabinoid enhancement of lncRNA MMP25-AS1/MMP25 interaction reduces neutrophil infiltration and intestinal epithelial injury in HIV/SIV infection
Lakmini S. Premadasa, … , Smita Kulkarni, Mahesh Mohan
Lakmini S. Premadasa, … , Smita Kulkarni, Mahesh Mohan
Published April 10, 2023
Citation Information: JCI Insight. 2023;8(7):e167903. https://doi.org/10.1172/jci.insight.167903.
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Cannabinoid enhancement of lncRNA MMP25-AS1/MMP25 interaction reduces neutrophil infiltration and intestinal epithelial injury in HIV/SIV infection

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Abstract

Intestinal epithelial barrier dysfunction, a hallmark of HIV/SIV infection, persists despite viral suppression by combination antiretroviral therapy (cART). Emerging evidence suggests a critical role for long noncoding RNAs (lncRNAs) in maintaining epithelial homeostasis. We simultaneously profiled lncRNA/mRNA expression exclusively in colonic epithelium (CE) of SIV-infected rhesus macaques (RMs) administered vehicle (VEH) or Δ-9-tetrahydrocannabinol (THC). Relative to controls, fewer lncRNAs were up- or downregulated in CE of THC/SIV compared with VEH/SIV RMs. Importantly, reciprocal expression of the natural antisense lncRNA MMP25-AS1 (up 2.3-fold) and its associated protein-coding gene MMP25 (attracts neutrophils by inactivating alpha-1 anti-trypsin/SERPINA1) (down 2.2-fold) was detected in CE of THC/SIV RMs. Computational analysis verified 2 perfectly matched complementary regions and an energetically stable (normalized binding free energy = –0.2626) MMP25-AS1/MMP25 duplex structure. MMP25-AS1 overexpression blocked IFN-γ–induced MMP25 mRNA and protein expression in vitro. Elevated MMP25 protein expression in CE of VEH/SIV but not THC/SIV RMs was associated with increased infiltration by myeloperoxidase/CD11b++ neutrophils (transendothelial migration) and epithelial CD47 (transepithelial migration) expression. Interestingly, THC administered in combination with cART increased MMP25-AS1 and reduced MMP25 mRNA/protein expression in jejunal epithelium of SIV-infected RMs. Our findings demonstrate that MMP25-AS1 is a potentially unique epigenetic regulator of MMP25 and that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury potentially by downregulating MMP25 expression through modulation of MMP25-AS1.

Authors

Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan

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