Browsing by Author "DeMarco, Todd"

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    Fast Dissemination of New HIV-1 CRF02/A1 Recombinants in Pakistan.
    (PLoS One, 2016) Chen, Yue; Hora, Bhavna; DeMarco, Todd; Shah, Sharaf Ali; Ahmed, Manzoor; Sanchez, Ana M; Su, Chang; Carter, Meredith; Stone, Mars; Hasan, Rumina; Hasan, Zahra; Busch, Michael P; Denny, Thomas N; Gao, Feng
    A number of HIV-1 subtypes are identified in Pakistan by characterization of partial viral gene sequences. Little is known whether new recombinants are generated and how they disseminate since whole genome sequences for these viruses have not been characterized. Near full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes or next generation sequencing from 34 HIV-1-infected individuals in Pakistan. Phylogenetic tree analysis showed that the newly characterized sequences were 16 subtype As, one subtype C, and 17 A/G recombinants. Further analysis showed that all 16 subtype A1 sequences (47%), together with the vast majority of sequences from Pakistan from other studies, formed a tight subcluster (A1a) within the subtype A1 clade, suggesting that they were derived from a single introduction. More in-depth analysis of 17 A/G NFLG sequences showed that five shared similar recombination breakpoints as in CRF02 (15%) but were phylogenetically distinct from the prototype CRF02 by forming a tight subcluster (CRF02a) while 12 (38%) were new recombinants between CRF02a and A1a or a divergent A1b viruses. Unique recombination patterns among the majority of the newly characterized recombinants indicated ongoing recombination. Interestingly, recombination breakpoints in these CRF02/A1 recombinants were similar to those in prototype CRF02 viruses, indicating that recombination at these sites more likely generate variable recombinant viruses. The dominance and fast dissemination of new CRF02a/A1 recombinants over prototype CRF02 suggest that these recombinant have more adapted and may become major epidemic strains in Pakistan.
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    Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection.
    (Journal of virology, 2023-10) Evangelous, Tyler D; Berry, Madison; Venkatayogi, Sravani; LeMaster, Cas; Geanes, Eric S; De Naeyer, Nicole; DeMarco, Todd; Shen, Xiaoying; Li, Hui; Hora, Bhavna; Solomonis, Nicholas; Misamore, Johnathan; Lewis, Mark G; Denny, Thomas N; Montefiori, David; Shaw, George M; Wiehe, Kevin; Bradley, Todd; Williams, Wilton B
    We recently found that a new pathogenic chimeric simian-human immunodeficiency virus (SHIV) elicited heterologous human immunodeficiency virus type-1 (HIV-1) neutralizing antibodies (nAbs) in therapy-naïve young rhesus macaques (RMs) following neonatal SHIV infection. Moreover, a subset of the SHIV-infected young RMs spontaneously controlled viremia. Here we evaluated humoral and cellular immunity and plasma biomarkers associated with spontaneous viremia suppression in a new model of young SHIV-infected RMs that generated heterologous HIV-1 nAbs independent of viremia control to gain insights into pediatric immunity that may be harnessed by appropriate therapies in HIV-1-infected infants and children. We determined the levels of 31 plasma analytes (cytokines, chemokines, and growth factors) in SHIV-infected RMs over the course of infection and found that six analytes with chemoattractant or pro-inflammatory activities had significantly lower levels in plasma of RMs that controlled viremia compared to non-controllers. Single-cell transcriptomics of blood-derived immune cells demonstrated that RMs with viremia control had upregulated genes associated with immune activation and cytotoxic functions, whereas non-controllers had upregulated genes associated with immune cell exhaustion and dysfunction. In addition to CD8 T and natural killer cells, monocytes with upregulation of inhibitory genes previously reported only in cytotoxic cells constituted the immunologic environment associated with viremia suppression. These data implicated a complex immunologic milieu of viremia suppression that is not fully defined in pediatric subjects. Understanding immune cell subsets that may be harnessed to control viremia will provide insights into future designs of HIV-1 therapeutic strategies. IMPORTANCE Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.
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    Increased predominance of HIV-1 CRF01_AE and its recombinants in the Philippines.
    (The Journal of general virology, 2019-01-24) Chen, Yue; Hora, Bhavna; DeMarco, Todd; Berba, Regina; Register, Heidi; Hood, Sylvia; Carter, Meredith; Stone, Mars; Pappas, Andrea; Sanchez, Ana M; Busch, Michael; Denny, Thomas N; Gao, Feng
    The growth rate of new HIV infections in the Philippines was the fastest of any countries in the Asia-Pacific region between 2010 and 2016. To date, HIV-1 subtyping results in the Philippines have been determined by characterizing only partial viral genome sequences. It is not known whether recombination occurs in the majority of unsequenced genome regions. Near-full-length genome (NFLG) sequences were obtained by amplifying two overlapping half genomes from plasma samples collected between 2015 and 2017 from 23 newly diagnosed infected individuals in the Philippines. Phylogenetic analysis showed that the newly characterized sequences were CRF01_AE (14), subtype B (3), CRF01/B recombinants (5) and a CRF01/CRF07/B recombinant (1). All 14 CRF01_AE formed a tight cluster, suggesting that they were derived from a single introduction. The time to the most recent common ancestor (tMRCA) for CRF01_AE in the Philippines was 1995 (1992-1998), about 10-15 years later than that of CRF01_AE in China and Thailand. All five CRF01/B recombinants showed distinct recombination patterns, suggesting ongoing recombination between the two predominant circulating viruses. The identification of partial CRF07_BC sequences in one CRF01/CRF07/B recombinant, not reported previously in the Philippines, indicated that CRF07_BC may have been recently introduced into that country from China, where CRF07_BC is prevalent. Our results show that the major epidemic strains may have shifted to an increased predominance of CRF01_AE and its recombinants, and that other genotypes such as CRF07_BC may have been introduced into the Philippines.
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    Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection.
    (Science translational medicine, 2022-09) Saunders, Kevin O; Edwards, Robert J; Tilahun, Kedamawit; Manne, Kartik; Lu, Xiaozhi; Cain, Derek W; Wiehe, Kevin; Williams, Wilton B; Mansouri, Katayoun; Hernandez, Giovanna E; Sutherland, Laura; Scearce, Richard; Parks, Robert; Barr, Maggie; DeMarco, Todd; Eater, Chloe M; Eaton, Amanda; Morton, Georgeanna; Mildenberg, Benjamin; Wang, Yunfei; Rountree, R Wes; Tomai, Mark A; Fox, Christopher B; Moody, M Anthony; Alam, S Munir; Santra, Sampa; Lewis, Mark G; Denny, Thomas N; Shaw, George M; Montefiori, David C; Acharya, Priyamvada; Haynes, Barton F
    A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID50 titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4+ T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine-induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env.