Browsing by Author "Parrish, Nicholas F"
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Item Unknown Neutralization properties of simian immunodeficiency viruses infecting chimpanzees and gorillas.(MBio, 2015-04-21) Barbian, Hannah J; Decker, Julie M; Bibollet-Ruche, Frederic; Galimidi, Rachel P; West, Anthony P; Learn, Gerald H; Parrish, Nicholas F; Iyer, Shilpa S; Li, Yingying; Pace, Craig S; Song, Ruijiang; Huang, Yaoxing; Denny, Thomas N; Mouquet, Hugo; Martin, Loic; Acharya, Priyamvada; Zhang, Baoshan; Kwong, Peter D; Mascola, John R; Verrips, C Theo; Strokappe, Nika M; Rutten, Lucy; McCoy, Laura E; Weiss, Robin A; Brown, Corrine S; Jackson, Raven; Silvestri, Guido; Connors, Mark; Burton, Dennis R; Shaw, George M; Nussenzweig, Michel C; Bjorkman, Pamela J; Ho, David D; Farzan, Michael; Hahn, Beatrice HUNLABELLED: Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection. IMPORTANCE: SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.Item Unknown Phenotypic properties of transmitted founder HIV-1.(Proc Natl Acad Sci U S A, 2013-04-23) Parrish, Nicholas F; Gao, Feng; Li, Hui; Giorgi, Elena E; Barbian, Hannah J; Parrish, Erica H; Zajic, Lara; Iyer, Shilpa S; Decker, Julie M; Kumar, Amit; Hora, Bhavna; Berg, Anna; Cai, Fangping; Hopper, Jennifer; Denny, Thomas N; Ding, Haitao; Ochsenbauer, Christina; Kappes, John C; Galimidi, Rachel P; West, Anthony P; Bjorkman, Pamela J; Wilen, Craig B; Doms, Robert W; O'Brien, Meagan; Bhardwaj, Nina; Borrow, Persephone; Haynes, Barton F; Muldoon, Mark; Theiler, James P; Korber, Bette; Shaw, George M; Hahn, Beatrice HDefining the virus-host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.Item Open Access Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity.(Nature communications, 2018-04) Joas, Simone; Parrish, Erica H; Gnanadurai, Clement W; Lump, Edina; Stürzel, Christina M; Parrish, Nicholas F; Learn, Gerald H; Sauermann, Ulrike; Neumann, Berit; Rensing, Kerstin Mätz; Fuchs, Dietmar; Billingsley, James M; Bosinger, Steven E; Silvestri, Guido; Apetrei, Cristian; Huot, Nicolas; Garcia-Tellez, Thalia; Müller-Trutwin, Michaela; Hotter, Dominik; Sauter, Daniel; Stahl-Hennig, Christiane; Hahn, Beatrice H; Kirchhoff, FrankHIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.