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V M Hirsch

Publications and source records attributed to V M Hirsch.

At least 55 records · Page 3Linked to original sources
PubMed1995

Phylogeny and natural history of the primate lentiviruses, SIV and HIV.

Studies of primate lentivirus phylogeny over the past decade have established a minimum of five related, but genetically distinct, groups of simian immunodeficiency virus (SIV), each originating from a different African primate species. The hypothesis that HIV-2 (and SIVmac) arose by cross-species transmission from sooty mangabeys (Cercocebus atys has been strengthened by a more detailed characterization of the SIVsm/SIVmac/HIV-2 group of viruses. SIV from all four subspecies of African green monkeys (SIVagm) have been characterized with an apparent chimeric genome structure of SIVagm from West African green monkeys. Although these naturally infected primates remain healthy, cross-species transmission to other primate species may result in immunodeficiency, as caused by SIVsm infection of macaque monkeys (Macaca sp.) and recently, SIVagm infection of pig-tailed macaques (M. nemestrina). Studies of variation within infected individuals have been facilitated by adaptation of the techniques of heteroduplex analysis and single-stranded conformational polymorphism of PCR generated fragments.

Africa↗
PubMed1995

Receptor function of CD4 structures from African green monkey and pig-tail macaque for simian immunodeficiency virus, SIVsm, SIVagm, and human immunodeficiency virus type-1.

Differences in kinetics of infection, cellular tropism, and cytopathology of SIV and HIV appear to depend on both viral and host factors. We investigated the role of critical CD4 structures from African green monkeys (AGM) a natural SIV host, from pig-tailed macaques (PT) an unnatural SIV host, and from humans, as well as the role of species-specific cellular factors involved in the tropism, kinetics of infection, and cytopathic effects of several SIV and HIV-1. Critical regions of the PT macaque and AGM CD4 genes (V1, V1J1, and V1J1V2J2) were stably expressed as chimeras with the human CD4 gene in human (HeLa and 293) and macaque (CMMT) cell lines. CD4 expressing cell lines were used for infection studies with cell-free SIVsm, SIVmac, SIVsmmPBj, SIVagm, and HIV-1. Results show that both PT CD4 and AGM CD4 supported infection with comparable infection kinetics by all SIV or HIV-1 strains tested. Although structural analysis predicted a major change in secondary structure of AGM CD4/CDR-3, these structural changes did not influence the degree of syncytia formation induced by several SIV and HIV-1. However, the cell line used to express the CD4 gene appeared to be a critical determinant of infection. Thus, SlV strains did not infect human cell lines regardless of the CD4 expressed in these cells. In contrast, HIV-1 did not infect any macaque cell line. This study demonstrates that the differences in CD4 structure among different primate species are clearly not responsible for differences in SIV and HIV infection kinetics, tropism, and cytopathology. However, species-specific factor(s), presumably expressed on the cell surface, markedly influences the ability of SIV or HIV to infect cells expressing CD4.

Amino Acid Sequence↗
PubMed1995

Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication.

Previous studies suggested that simian immunodeficiency viruses isolated from African green monkeys (SIVagm) are relatively nonpathogenic. The report describes the isolation and biologic and molecular characterization of a pathogenic SIVagm strain derived from a naturally infected African green monkey. This virus induced an AIDS-like syndrome characterized by early viremia, frequent thrombocytopenia, severe lymphoid depletion, opportunistic infections, meningoencephalitis, and death of five of eight macaques within 1 year after infection. An infectious clone derived from this isolate reproduced the immunodeficiency disease in pig-tailed (PT) macaques, providing definitive proof of the etiology of this syndrome. Although the virus was highly pathogenic in PT macaques, no disease was observed in experimentally infected rhesus macaques and African green monkeys despite reproducible infection of the last two species. Whereas infection of PT macaques was associated with a high viral load in plasma, peripheral blood mononuclear cells, and tissues, low-level viremia and infrequent expression in lymph nodes of rhesus macaques and African green monkeys suggest that differences in pathogenicity are associated with the extent of in vivo replication. The availability of a pathogenic molecular clone will provide a useful model for the study of viral and host factors that influence pathogenicity.

Animals↗
PubMed1994

Complement control proteins, CD46, CD55, and CD59, as common surface constituents of human and simian immunodeficiency viruses and possible targets for vaccine protection.

Complement control proteins include a group of membrane-bound surface antigens that protect cells from complement lysis by preventing formation of the membrane attack complex (MAC) of complement. HIV-1 and SIV are known to possess cellular proteins, making it possible that some of them contribute to the ability of these viruses to evade complement lysis. Three complement control proteins, CD46 (membrane cofactor protein), CD55 (decay accelerating protein), and CD59 (HRF20), were found by flow cytometry to be expressed on the surface of CD4+ cell lines commonly used for HIV-1 and SIV synthesis. Monoclonal antibodies to each of these proteins precipitated HIV-1 IIIB and SIV delta/B670 synthesized in CEM x 174 cells and two primary HIV-1 isolates synthesized in peripheral blood mononuclear cells, indicating that CD46, CD55, and CD59 are physically associated with the virus membrane after the virus has been released from the surface of infected cells. Additional experiments showed that the precipitated material contained infectious virus, confirming that whole virus was precipitated. Evidence that CD46 and CD59 are immunogenic in macaques was found when anti-cell antibodies in plasmas from macaques immunized with human cell-grown SIV blocked anti-CD46 and anti-CD59 from binding to the surface of CEM x 174 cells. Anti-cell antibodies rendered HIV-1 susceptible to complement lysis as measured by the release of p24 core protein, and consistently produced a complement-dependent reduction in HIV-1 and SIV infectivity of 1-3 logs. These results demonstrate that CD46, CD55, and CD59 are common surface constituents of HIV-1 and SIV. The results also raise the possibility that the mechanism of SIV vaccine protection attributed to anti-cell antibodies could have involved complement-mediated virolysis.

Antibodies, Viral↗
PubMed1994

Nucleotide sequence analysis of puma lentivirus (PLV-14): genomic organization and relationship to other lentiviruses.

The complete nucleotide sequence of an isolate of puma lentivirus (PLV-14) was obtained by an inverse polymerase chain reaction (I-PCR) technique and confirmed by conventional PCR. Both methods were used to amplify overlapping regions of proviral DNA, for cloning and sequencing, from genomic DNA isolated from PLV-14 infected Florida puma (Felis concolor coryi) peripheral blood mononuclear cells (PBMC). The provirus has a total length of 9100 nucleotides and the genomic organization of presumed protein coding regions are similar to those seen in other members of the lentivirus family, i.e., three large open reading frames gag, pol, and env as well as smaller intergenic regions that apparently encode regulatory proteins vif and 3' rev by positional and sequence similarity to those seen in other lentiviruses. Two additional open reading frames were identified in the env region and their function (if any) is unknown. The length of the PLV-14 long terminal repeat (LTR) was found to be shorter than the LTRs of feline immunodeficiency virus (FIV). The sequence homology between PLV-14 and other lentiviruses demonstrates that PLV-14 is most closely related to FIV from domestic cats. However, the extent of sequence divergence of each retroviral gene segment is large (e.g., percentage sequence similarity between FIV and PLV-14 env is 8% amino acid and 37% nucleotide similarity), indicating relatively ancient divergence of these feline lentiviral genomes.

Amino Acid Sequence↗
PubMed1994

Mosaic genome structure of simian immunodeficiency virus from west African green monkeys.

Elucidation of the phylogenetic origins of simian and human immunodeficiency viruses (SIV and HIV) is fundamental to the understanding of HIV pathogenesis and the spread of AIDS worldwide. In this study, we molecularly characterized multiple SIVAGM isolates from four different African green monkey species (vervet, grivet, sabaeus and tantalus monkeys). Phylogenetic analysis of partial (1 kb) env sequences indicated that all SIVAGM strains cluster together, and that they fall into four distinct sequence sub-groups according to their species of origin. However, alignment of long terminal repeat sequences revealed that SIVs from West African sabaeus monkeys contain a structural feature (a duplication of the transactivation response element) thus far only found in otherwise highly divergent lentiviruses infecting sooty mangabeys (SIVSM) and humans (HIV-2). To determine whether there were additional similarities with the SIVSM/HIV-2 group, a full-length replication competent sabaeus provirus was cloned and sequenced. In phylogenetic trees derived from the central and 3' coding regions, the sabaeus virus clustered with SIVAGM isolates from other African green monkey species. However, in trees derived from the 3' half of gag and the adjacent 5' region of pol, the sabaeus virus grouped with the SIVSM/HIV-2 lineage. These results indicated that the sabaeus virus comprised a mosaic genome which must have resulted from recombination of divergent lentiviruses in the distant past. A second, independent sabaeus isolate exhibited similar phylogenetic relationships, suggesting that all West African green monkey viruses share this complex evolutionary history. Taken together, these results indicate that African green monkeys have been infected with SIVAGM for very long periods of time, and that recombination and cross-species transmission in the wild have contributed to the genetic complexity of primate lentiviruses.

Africa, Western↗
PubMed1994

Pathogenic diversity of simian immunodeficiency viruses.

The SIV family is a diverse group of viruses that vary considerably in pathogenesis and virulence in their natural host species or macaques. Although the disease induced by the SIVsm subtype in particular is remarkably similar to human AIDS, it must be remembered that this is an experimental animal model. Therefore, although the pathogenesis of SIVsm (and other viruses) in macaques offers an relevant animal model for pathogenesis and vaccine trials, the interactions of these viruses in their natural host, and virus-, or host-specific effects have been poorly characterized. This animal model offers a unique opportunity to study the details of the pathogenesis of immunodeficiency and to define host and viral factors responsible for disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Prolonged clinical latency and survival of macaques given a whole inactivated simian immunodeficiency virus vaccine.

Simian immunodeficiency virus (SIV) infection of macaques is a useful and relevant model for evaluating candidate human immunodeficiency virus (HIV) vaccines. One important feature of this model is that SIV vaccines can be evaluated for their ability to prevent infection as well as to prevent or delay the onset of AIDS. In the present study, a group of macaques was vaccinated with whole inactivated SIV and challenged with peripheral blood mononuclear cells from an SIV-infected macaque. This challenge represented a rigorous and realistic test of the immunization protocol. All macaques became infected after challenge; however, immunized animals survived significantly longer (P < .03) than naive controls. These data suggest that similar vaccines administered to humans at risk for HIV-1 infection might delay or prevent AIDS even if the vaccine failed to prevent infection.

AIDS Vaccines↗
PubMed1994

Spontaneous substitutions in the vicinity of the V3 analog affect cell tropism and pathogenicity of simian immunodeficiency virus.

Simian immunodeficiency virus (SIV) exists within tissues of infected macaques as a mixture of diverse genotypes. The goal of this study was to investigate the biologic significance of this variation in terms of cellular tropism and pathogenicity. PCR was used to amplify and clone 3'-half genomes from the spleen of an immunodeficiency SIV-infected pig-tailed macaque (Macaca nemestrina). Eight infectious clones were generated by ligation of respective 3' clones into a related SIVsm 5' clone, and virus stocks were generated by transient transfection. Four of these viruses were infectious for macaque peripheral blood mononuclear cells (PBMC) or monocyte-derived macrophages (MDM). Three viruses with distinct tropism for macaque PBMC or MDM were tested for in vivo infectivity and pathogenicity. The ability of these three viruses to infect PBMC and macrophages correlated with differences in infectivity and pathogenicity. Thus, a virus that was infectious for both PBMC and MDM was highly infectious for macaques and induced AIDS in half of the inoculated animals. In contrast, virus that was less infectious for PBMC and not infectious for MDM induced only transient viremia. Finally, a virus that was not infectious for either primary cell type did not infect macaques. Chimeric clones exchanging portions of the envelope gene of the 62A and smH4 molecular clones and a series of point mutants were used to map the determinant of tropism to a 60-amino-acid region of gp120 encompassing the V3 analog of SIV. Naturally occurring mutations within this region were critical for determining tropism and, as a result, pathogenicity of these SIVsm clones.

Amino Acid Sequence↗
PubMed1994

Extensive envelope heterogeneity of simian immunodeficiency virus in tissues from infected macaques.

The extent of virus genetic variation within tissues and peripheral blood mononuclear cells (PBMC) from two simian immunodeficiency virus (SIV)-infected macaques was analyzed. The products of PCR amplification of two regions, region 1 (SIV V1 region) and region 2 (region corresponding to the human immunodeficiency virus V3 cysteine loop and part of the C3 region immediately downstream), of the SIV envelope were examined for single-stranded conformation polymorphism followed by sequence analysis of selected clones. The V1 region of the SIV envelope of viruses present within lymphoid tissues displayed extensive heterogeneity, while viral populations within the PBMC and brain appeared to be less variable. Region 2 heterogeneity in both animals was generally confined to three residues in a tissue-specific manner. In addition, virus from the brains of both animals appeared to be distinct compared with viruses present in other tissues and PBMC of the same animal, both in the pattern of PCR-single-stranded conformation polymorphism SCP and in the sequence of region 2. These studies revealed that the tissues of SIV-infected macaques were a reservoir for viral variants distinct from those seen in PBMC.

Amino Acid Sequence↗
PubMed1993

Identification of a new subgroup of SIVagm in tantalus monkeys.

Simian immunodeficiency viruses from African green monkeys (SIVagm) can be classified into three subgroups based upon the species from which they were isolated. The most extensively studied subgroup are composed of SIVagm isolated from vervet monkeys (Cercopithicus pygerythrus). Fewer isolates have been characterized from either grivets (Cercopithicus aethiops) or green monkeys (Cercopithicus sabeus). An additional distinct species of African green monkeys, tantalus monkeys (Cercopithicus tantalus), has not been characterized in terms of SIV infection. A high seroprevalence of SIV-specific antibodies was identified in sera collected from Ugandan tantalus monkeys. SIV was isolated from PBMC (SIVagm/tan), the gag region amplified by polymerase chain reaction, cloned, and sequenced. Based upon gag, SIVagm/tan isolates cluster genetically with other previously recognized SIVagm strains. However, SIVagm from tantalus monkeys forms a distinct genetic subgroup. These data confirm earlier observations of species-specific subtypes of SIVagm viruses and support the hypothesis that these viruses may have coevolved with their host during geographic dispersion throughout Africa.

Amino Acid Sequence↗
PubMed1993

Genetic variation of the SIVagm transmembrane glycoprotein in naturally and experimentally infected primates.

OBJECTIVE: An in-frame stop codon prematurely truncating the transmembrane glycoprotein (TMP) is a common feature of many simian immunodeficiency virus, African green monkey strain (SIVagm) molecular clones. The purpose of this study was to investigate the native form of the SIVagm TMP in a naturally infected African green monkey (AGM) and to study the fate of the stop codon following the passage of SIVagm in primates. DESIGN: Polymerase chain reaction was used to clone the entire intracellular portion of the TMP from: (1) peripheral blood mononuclear cells (PBMC) of the naturally infected AGM 155; (2) an isolate of SIVagm155 in rhesus PBMC and (3) PBMC from pig-tailed macaques and AGM experimentally infected with an SIVagm molecular clone encoding a truncated TMP. RESULTS: PBMC of the naturally infected AGM contained a 'swarm' of related virus genotypes that encoded a full-length TMP, whereas tissue-culture passage in rhesus PBMC resulted in a prematurely truncated form of the TMP. This premature stop codon persisted in PBMC of monkeys experimentally infected with an SIVagm molecular clone. Both macaques and AGM of same subspecies as AGM 155 (Cercopithecus pygerythrus) and other subspecies (C. aethiops and C. sabaeus) became infected with SIVagm155. Genetic drift of this region of env, as assessed by calculation of the nucleotide substitution/site/year rate, was similar to that of other retroviruses. CONCLUSIONS: The native form of the SIVagm TMP is a full-length gp40, similar to the SIV macaque (SIVmac) strain and HIV-1. However, passage of SIVagm in tissue culture can result in point mutations that introduce a premature stop codon. This stop codon persists during subsequent in vivo passage of SIVagm in primates. This contrasts with similar studies in macaques infected with SIVmac, in which reversion of the TMP stop codon was observed.

Amino Acid Sequence↗
PubMed1993

A distinct African lentivirus from Sykes' monkeys.

Asymptomatic infection with simian immunodeficiency virus (SIV) has been demonstrated in African Sykes' monkeys (Cercopithecus mitis albogularis), and virus isolation confirmed infection with a novel SIV from Sykes' monkeys (SIVsyk). Macaques inoculated with SIVsyk became persistently infected but remained clinically healthy. We utilized polymerase chain reaction amplification to generate a full-length, infectious molecular clone of SIVsyk. The genome organization of SIVsyk is similar to that of the other primate lentiviruses, consisting of gag, pol, vif, vpr, tat, rev, env, and nef. A unique feature is the absence of the highly conserved NF-kappa B binding site in the long terminal repeat. SIVsyk is genetically equidistant from other primate lentiviruses. Thus, SIVsyk represents a new group that is distinct from the four previously recognized primate lentivirus groups: human immunodeficiency virus type 1 (HIV-1), SIV from sooty mangabeys (SIVsmm) and HIV-2, SIV from African green monkeys (SIVagm), and SIV from mandrills (SIVmnd). The genetic differences between SIVsyk and SIVagm, isolates derived from monkeys of the same genus, underscore the potential for other distinct SIVs which have yet to be isolated and characterized.

Africa↗
PubMed1993

Multiple viral determinants contribute to pathogenicity of the acutely lethal simian immunodeficiency virus SIVsmmPBj variant.

Simian immunodeficiency virus (SIV) induces an immunodeficiency syndrome similar to human AIDS. Although the disease course of SIV-induced immunodeficiency is generally measured in months to years, a disease syndrome that results in death in 5 to 14 days has been described in pig-tailed macaques infected with the SIVsmmPBj (PBj) strain. The purpose of this study was to derive an acutely lethal PBj molecular clone in order to study viral genes involved in pathogenesis. Six infectious molecular clones were generated; acutely fatal disease was induced by experimental inoculation of pig-tailed macaques with virus stocks derived from either of two clones, PBj6.6 or PBj14.6. Molecular chimeras were constructed by exchange of regions of the genome of PBj6.6 and a nonlethal, related clone, SIVsmH4. Only a chimera expressing the PBj genome under the control of a SIVsmH4 long terminal repeat induced death soon after inoculation. These studies suggest that multiple viral genes of PBj are critical for development of acute disease. More specifically, the env gene but not the long terminal repeat PBj was required for acute disease induction; however env must act in concert with another gene(s) of the PBj genome.

Animals↗
PubMed1992

Cloning and sequences of primate CD4 molecules: diversity of the cellular receptor for simian immunodeficiency virus/human immunodeficiency virus.

To study the interaction between the primate lentiviruses simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) and the CD4 receptor we have cloned and sequenced the CD4 molecule from six non-human primate species: African green monkeys (three subspecies: sabeus, pytherethrus, aethiops), sooty mangabeys, patas monkeys, chimpanzees, rhesus macaques, and pig-tail macaques. Molecular cDNA clones representing CD4 mRNA were generated from total RNA from peripheral blood mononuclear cells (PBMC) by polymerase chain reaction (PCR) amplification including reverse transcriptase in initial reactions followed by two rounds of nested amplifications. Primer sequences were selected from regions conserved among human and rodent CD4 genes. Alignments of deduced amino acid sequences revealed interesting findings. First, all of the primate CD4 molecules were about 90% identical to the human CD4 sequence except the chimpanzee (98%). Second, two macaques or two African green monkey subspecies were as distanly related as the human versus chimpanzee sequences. Third, relatedness of CD4 sequences could not be predicted on the basis of geographic origin (Asian vs. African). Finally, upon sequencing several clones from individual monkeys, a low degree of sequence variation (nucleotide substitutions, deletions, and insertions) was found within the same animal, and in case of sooty mangabeys two distict populations of CD4 molecules were present within three of four individuals. The distinguishing features involved eight amino acid changes, including a single lysine deletion relative to a primate consensus sequence in the first complementary-determing region of V1J1. These two CD4 populations were present also at the genomic DNA level and may arrive from the two chromosomal alleles, suggesting the existence of distinct sooty mangabey subspecies. Overall, the V1J1 and to a lesser extent V2J2 were the most variable regions among the sequences examined. By construction and expression in mammalian cell lines of CD4 chimeras in which these regions of the human CD4 were replaced by those of the African green monkey and pig-tail macaques, a higher molecular mass of the CD4 chimeras were obtained in sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the additional N-linked glycosylation sites present in these monkey CD4 are also used.

Amino Acid Sequence↗
PubMed1992

SIV from stump-tailed macaques: molecular characterization of a highly transmissible primate lentivirus.

Over the past 6 years, simian immunodeficiency viruses (SIVs) have been isolated from four distinct species of macaques (Macaca mulatta, M. fascicularis, M. nemestrina, and M. arctoides) in captivity in the United States. However, the epidemiologic and genetic relationships among SIVs from the four species are not well understood. SIV from stump-tailed macaques (M. arctoides) (SIVstm) is unusual in that it has been associated with outbreaks of infection characterized by aggressive spread within stump-tailed macaque colonies at two separate primate centers in the United States. To characterize SIVstm at the molecular level, we have derived six biologically active viral DNA clones by polymerase chain reaction amplification of genomic DNA from infected cells. Nucleotide sequence analyses of one clone (SIVstm/37.16) showed that SIVstm was indeed a member of the previously defined group of simian lentiviruses that are closely related to the human immunodeficiency virus type 2 (HIV-2). However, our data indicate that SIVstm is equidistantly related to the other SIVs from macaques (SIVmac 251/142 and SIVmne) and SIV from African sooty mangabeys (SIVsmm). These findings suggest that SIV from captive macaques may have originated from several cross-species transmissions from imported sooty mangabeys and that additional spread has been fostered by the exchange of macaques among primate centers.

Amino Acid Sequence↗