Effects of natural sequence variation on recognition by monoclonal antibodies neutralize simian immunodeficiency virus infectivity

Choi, Weon Sang; Collignon, Catherine; Thiriart, Clotilde; Burns, D. P. W.; Stott, E. J.; Kent, Karen; Desrosiers, Ronald C.

doi:10.1128/jvi.68.9.5395-5402.1994

Cited by 41 publications

(22 citation statements)

References 38 publications

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“…Evolution of V1 includes expansion and contraction of three-nucleotide repeats and a tightly clustered patch of amino acid replacements. The haplotype analysis revealed a remarkable level of in-frame insertions and deletions in the V1 loop, similar to reports of other SIV mac -infected animals (30,31,43). In TP2, insertions were found at four different loci within a short span of 13 residues (positions 126 to 139), rich in serine and threonine residues coded for by TCA and ACA codons ( Fig.…”

Section: Resultssupporting

confidence: 85%

“…and rising as high as 95.8% at 18 weeks p.i. It has been reported that deletions spanning P421 in V4 can result in loss of recognition by V4-specific antibodies (31). Thus, the emergence of Δ 423 ERHR 426 in two animals in our cohort, the rise to high frequency early in infection, and the persistence of this deletion variant over several weeks of replication (to high levels within TP2) together suggest that early Env-specific antibody responses target either the V4 loop or a conformational epitope spanning the V4 loop region.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of env sequence by bulk PCR and cloning of env sequences isolated from chronically SIV-infected macaques has revealed evidence for positive selection, specifically in the V1 and V4 loops (17,29,30). Variation in V1 and V4 was similarly observed in other SIV/macaque models of infection, including SIV mac 251 infection of rhesus macaques, SIV mne infection of pig-tailed macaques, and SIV sm infection of rhesus macaques (31)(32)(33)(34)(35)(36)(37)(38)(39), as well as in the context of natural infection in sooty mangabeys (40). More recently, an analysis of env sequence variation in an animal with a potent NAb response to the parental challenge strain, SIV mac 239, identified individual substitutions within the V1 and V4 loop that, when introduced into SIV mac 239, provided resistance to the high-titer neutralizing plasma (17).…”

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confidence: 89%

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High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses

Ita

Hill

Lam

et al. 2018

J Virol

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Primate lentiviruses, including the human and simian immunodeficiency viruses (HIV and SIV), produce infections marked by persistent, ongoing viral replication. This occurs despite the presence of virus-specific adaptive immune responses, including antibodies targeting the viral envelope glycoprotein (Env), and evolution of antibody-escape variants is a well-documented feature of lentiviral infection. Here, we examined the evolutionary dynamics of the SIV gene during early infection (≤29 weeks postinfection) in a cohort of four SIV251-infected rhesus macaques. We tracked evolution during acute and early infection using frequent sampling and ultradeep sequencing of viral populations, capturing a transmission bottleneck and the subsequent reestablishment of Env diversity. A majority of changes in the gp120 subunit mapped to two short clusters, one in the first variable region (V1) and one in V4, while most changes in the gp41 subunit appeared in the cytoplasmic domain. Variation in V1 was dominated by short duplications and deletions of repetitive sequence, while variation in V4 was marked by short in-frame deletions and closely overlapping substitutions. The most common substitutions in both patches did not alter viral replicative fitness when tested using a highly sensitive, deep-sequencing-based competition assay. Our results, together with the observation that very similar or identical patterns of sequence evolution also occur in different macaque species infected with related but divergent strains of SIV, suggest that resistance to early, strain-specific anti-Env antibodies is the result of temporally and mutationally predictable pathways of escape that occur during the early stages of infection. The envelope glycoprotein (Env) of primate lentiviruses mediates entry by binding to host cell receptors followed by fusion of the viral membrane with the cell membrane. The exposure of Env complexes on the surface of the virion results in targeting by antibodies, leading to selection for virus escape mutations. We used the SIV/rhesus macaque model to track evolution of variation in Env during acute/early infection in animals with and without antibody responses to Env, uncovering remarkable variation in animals with antibody responses within weeks of infection. Using a deep-sequencing-based fitness assay, we found substitutions associated with antibody escape had little to no effect on inherent replicative capacity. The ability to readily propagate advantageous changes that incur little to no replicative fitness costs may be a mechanism to maintain continuous replication under constant immune selection, allowing the virus to persist for months to years in the infected host.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 89%

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High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses

Ita

Hill

Lam

et al. 2018

J Virol

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“…All peptides were based on the consensus sequence of the 32H isolate of SIVmac251 [1] and the sequences corresponding to each peptide are listed in Table 1 (gp120) and Table 2 (gp41). The designation of variable and conserved regions of SIV gp120 are based on those reported by Choi et al [3], and regions of SIV gp41 were named by analogy with HIV-1 gp41 [10].…”

Section: Siv Antibody Assaysmentioning

confidence: 99%

“…SIV gp120 peptides used in this study Assignment of variable and conserved regions of SIV gp120 differs slightly from HIV-1 and are adapted from those designated by Choi et al[3]; the Cys loop designation for peptides 29-32 correspond to the V3 cysteine loop which is variable in HIV-1[10].…”

mentioning

confidence: 99%

Maturation of envelope‐specific antibody responses to linear determinants in monkeys inoculated with attenuated SIV

Cole

Paliotti

Murphey‐Corb

et al. 2000

J of Medical Primatology

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We have previously used a panel of quantitative and qualitative serological assays to define a lengthy and complex maturation of envelope-specific antibody responses in monkeys experimentally infected with attenuated simian immunodeficiency virus (SIV) that is closely associated with the temporal development of enduring and protective immunity to experimental virus challenge. To elucidate in more detail the changes in antibody specificity associated with this maturation, we describe here 'domain-specific' serological studies to characterize the evolution of antibody responses to defined linear determinants of the SIV envelope protein. The results of these studies reveal for the first time distinguishing differences in the evolution of antibody populations to distinct envelope peptide segments, as determined by measurements of antibody titer and avidity, indicating different patterns of antibody maturation to distinct linear envelope antigenic determinants. Thus, these data demonstrate the potential for domain-specific serology to produce a high-resolution characterization of SIV-specific antibody responses that can be used to evaluate experimental vaccine responses and to identify potential immune correlates of protection.

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Antibodies That Neutralize SIVmac251 in T Lymphocytes Cause Interruption of the Viral Life Cycle in Macrophages by Preventing Nuclear Import of Viral DNA

et al. 2001

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Previous reports from our lab had shown that sera obtained from SIV(mac)-infected animals neutralized SIV(mac) infectivity in CD4(+) T cells but failed to protect monkey primary macrophages from infection with the virus. However, the antibodies could inhibit completion of the viral life cycle in the macrophages at the postentry stage(s). In this report we examined the mechanisms of the late effect of the antibodies. Using monoclonal antibodies (MAbs), we demonstrated that only antibodies to the SIV envelope protein (KK17 and KK42) but not antibody to the viral core protein (FA2) had the same inhibitory effect as that of the anti-SIV sera. To identify the stage of the viral replication cycle that was inhibited by anti-SIV antibodies in macrophages, we used various PCR techniques to study viral entry/reverse transcription (by amplifying the viral gag gene), viral genome nuclear transport (by amplifying 2-LTR circular forms), viral integration (by Alu-PCR assay), and viral protein expression (by RIPA). We found that in macrophage cultures inoculated with SIV(mac)251 that were preincubated with antienvelope MAbs, viral DNA was detected at 8 h postinoculation but the 2-LTR circular forms and integrated viral DNAs were undetectable, and viral proteins were not expressed in these infected macrophages. These results strongly suggested that anti-SIV antibodies inhibited SIV(mac) replication in macrophages by blocking nuclear transport of viral genomes since viral DNA could not be detected in the nuclei of treated cultures. Furthermore, we showed that although viral replication in macrophages was interrupted by the antibodies, when cocultured with permissive T cells, the viral genomes presented in the cytoplasm of the macrophages could readily transfer to T cells during cell-cell contact. Importantly, this transfer could not be prevented by the antibodies. These results might explain the failure of passive antibody immunization against SIV(mac)251--a critical obstacle in AIDS vaccine development.

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Effects of natural sequence variation on recognition by monoclonal antibodies neutralize simian immunodeficiency virus infectivity

Cited by 41 publications

References 38 publications

High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses

High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses

Maturation of envelope‐specific antibody responses to linear determinants in monkeys inoculated with attenuated SIV

Antibodies That Neutralize SIVmac251 in T Lymphocytes Cause Interruption of the Viral Life Cycle in Macrophages by Preventing Nuclear Import of Viral DNA

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