Regional Clustering of Shared Neutralization Determinants on Primary Isolates of Clade C Human Immunodeficiency Virus Type 1 from South Africa

Bures, Renata; Morris, Lynn; Williamson, Carolyn; Ramjee, Gita; Deers, Mark; Fiscus, Susan A.; Karim, Salim Safurdeen. Abdool; Montefiori, David C.

doi:10.1128/jvi.76.5.2233-2244.2002

Cited by 114 publications

(114 citation statements)

References 82 publications

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“…In current studies, neutralization activity, against pseudoviruses expressing the homologous or randomly selected primary Env antigens, was detected in most of the post-immunization sera against approximately half of the viruses tested, independent of subtype. Not all homologous Env viruses showed high sensitivity to neutralization by post-immunization sera, which was not surprising given previous reports showing that infected HIV patient sera did not always have a high neutralizing activity against autologous viruses [46,47].…”

Section: Discussionmentioning

confidence: 53%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

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122

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An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6−001 in a Phase I clinical trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFNγ ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cellmediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

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Section: Discussionmentioning

confidence: 53%

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Wang

Kennedy

West

et al. 2008

Vaccine

Self Cite

122

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“…(20,21). Over the past few years, it has been demonstrated that clade C sera neutralizes autologous and heterologous clade C isolates, including geographically diverse isolates (22). This finding is consistent with the hypothesis that there is extensive sharing of epitopes within the HIV-1 B'/C intersubtype recombinant in China.…”

Section: Introductionsupporting

confidence: 78%

“…NAbs with cross-reactivity to multiple HIV-1 isolates could be lost as individuals become symptomatic. A number of factors have been previously reported to be positively associated with the breadth of HIV-1 broadly neutralizing activity, including a high CD4 + T cell count (13), and exposure to multiple viruses due to many partners (22). We analyzed the differences in the levels of CD4 + cell count and viral load between the asymptomatic and symptomatic individuals.…”

Section: Hiv-1 Primary Isolatementioning

confidence: 99%

Identification and characterization of broadly cross-reactive neutralizing antibodies in patients infected with HIV-1 B'/C recombinant (CRF07_BC)

et al. 2012

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Abstract. The identification of broadly cross-reactive neutralizing (BCN) antibodies is essential for the development of a more universally effective vaccine for human immunodeficiency virus (HIV). In this study, CRF07_BC serum was analyzed for cross-clade antibody reactivity and neutralization. A total of 117 HIV-1 sera (CRF07_BC) were screened for their capacity to neutralize three primary HIV-1 isolates. A total of 18 out of 117 sera cross-neutralized all three viruses, and were tested along with eight randomly selected non-BCN sera against seven primary HIV-1 isolates and two laboratory strains that represented different clades and tropisms. BCN sera neutralized eight or all nine of these primary isolates. Non-BCN sera did not display any broadly cross-reactive neutralizing responses. BCN sera neutralized with higher frequency and geometric mean titers compared to non-BCN sera. Sera from asymptomatic individuals on average neutralized a significantly greater number of the three key isolates than sera from symptomatic individuals. Our data indicate that the three HIV-1 isolated strains are sufficient to screen broad cross-neutralizing sera, and that BCN responses may contribute to protection from infection and disease progression. The neutralizing antibody response demonstrated extensive cross-neutralization, suggesting that neutralizing antibodies induced by vaccines will have a relatively low epitope diversity to overcome in patients infected with HIV-1 B'/C recombinant (CRF07_BC).

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“…In that regard, our structural BNAb analysis sharpens the focus of immunogen design targeted to the MPER. For example, although theoretically any antibody ligating this segment with high affinity might confer neutralizing activity, conformational variability and frequent mutations in the most prevalent genetic subtype C may limit immunogen design targeting the 2F5-like epitope (31). Given minimal membrane contribution to binding involving multiple solvent-exposed residues, a protein scaffold immunogen approach seems warranted in an attempt to elicit Z13e1-like antibodies.…”

Section: Discussionmentioning

confidence: 99%

Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface

Song¹,

Sun²,

Coleman³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

105

135

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A vaccine capable of stimulating protective antiviral antibody responses is needed to curtail the global AIDS epidemic caused by HIV-1. Although rarely elicited during the course of natural infection or upon conventional vaccination, the membrane-proximal ectodomain region (MPER) of the HIV-1 glycoprotein of M r 41,000 (gp41) envelope protein subunit is the target of 3 such human broadly neutralizing antibodies (BNAbs): 4E10, 2F5, and Z13e1. How these BNAbs bind to their lipid-embedded epitopes and mediate antiviral activity is unclear, but such information might offer important insight into a worldwide health imperative. Here, EPR and NMR techniques were used to define the manner in which these BNAbs differentially recognize viral membrane-encrypted residues configured within the L-shaped helix-hinge-helix MPER segment. Two distinct modes of antibody-mediated interference of viral infection were identified. 2F5, like 4E10, induces large conformational changes in the MPER relative to the membrane. However, although 4E10 straddles the hinge and extracts residues W672 and F673, 2F5 lifts up residues N-terminal to the hinge region, exposing L669 and W670. In contrast, Z13e1 effects little change in membrane orientation or conformation, but rather immobilizes the MPER hinge through extensive rigidifying surface contacts. Thus, BNAbs disrupt HIV-1 MPER fusogenic functions critical for virus entry into human CD4 T cells and macrophages either by preventing hinge motion or by perturbing MPER orientation. HIV-1 MPER features important for targeted vaccine design have been revealed, the implications of which extend to BNAb targets on other viral fusion proteins.membrane-proximal ectodomain region ͉ neutralizing antibody ͉ vaccine design ͉ AIDS ͉ fusion T he 120-nm-diameter HIV-1 is a retrovirus that has a small genome consisting of 9 genes. The enveloped virion surface expresses the trimeric glycoprotein of M r 160,000 (gp160) spike protein, whose gp120 and gp41 subunits are assembled into noncovalently associated heterodimers. Unlike gp120, each gp41 subunit has a transmembrane segment (TM) that inserts into the membrane of the virus. The membrane proximal ectodomain region (MPER) links this TM to the folded gp41 ectodomain. Entry of HIV-1 into human T cells is mediated by attachment of the gp120 subunit to receptor CD4 and then binding to the coreceptor (CCR5 or CXCR4) (1). These interactions result in structural rearrangement of the gp41 subunit, followed by fusion of viral and host cell membranes (2, 3). Thus, antibody-mediated protection against HIV-1 must target the gp120/gp41 envelope trimer, the only viral protein exposed on the virion surface.Although high-titer, strain-specific neutralizing antibodies are readily generated during the course of natural infection or against subunit vaccines, broadly neutralizing antibodies (BNAbs), in contrast, are rarely produced (reviewed in ref. 4). Sequence variability, extensive glycosylation, and immunodominance of those exposed, largely variable segments subvert immune res...

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Regional Clustering of Shared Neutralization Determinants on Primary Isolates of Clade C Human Immunodeficiency Virus Type 1 from South Africa

Cited by 114 publications

References 82 publications

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Identification and characterization of broadly cross-reactive neutralizing antibodies in patients infected with HIV-1 B'/C recombinant (CRF07_BC)

Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface

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