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L N Martin

Publications and source records attributed to L N Martin.

At least 37 records · Page 2Linked to original sources
PubMed1995

Distribution of SIV in lymph nodes of serially sacrificed rhesus monkeys.

Rhesus monkeys were inoculated with SIVDeltaB670 and sacrificed 2, 4, 8, and 24 weeks after inoculation or when moribund. Two monkeys predicted to have a rapid disease course and two predicted to have a slower disease course were sacrificed at each time point. Lymph nodes were studied by histopathology, immunohistochemistry, in situ hybridization, electron microscopy, flow cytometry for lymphocyte subsets, and mitogen responsiveness. A greater selective decrease in peripheral CD4+CD29+ (helper-inducer/memory) T cells occurred in monkeys with high antigenemia. Although the percentage of CD8+ lymphocytes was increased and the CD4+/CD8+ ratio decreased in all infected groups, there were no consistent differences between monkeys with high or low antigenemia in lymph node lymphocyte subsets. Blastogenic responses of lymph node lymphocytes to PHA, ConA, or PWM were not significantly altered in infected monkeys. A reticular pattern typical of antigen deposition within germinal center follicular dendritic cells was seen in three monkeys with atrophic lymph nodes, high serum antigenemia, and a low percentage of circulating CD4+/CD29+ cells. More individually stained cells were in monkeys with high serum antigen and in moribund animals. By in situ hybridization, most monkeys had signal in a reticular pattern of germinal centers. Animals with higher levels of serum antigenemia tended to have more infected cells and a more intense signal. Extracellular virions were found between the FDC foot processes in the germinal centers of lymph nodes. Disease course was already established 2 weeks after inoculation.

Animals↗
PubMed1995

Analysis of envelope glycoprotein-specific antibodies from SIV-infected and gp110-immunized monkeys in ACC and ADCC assays.

Sera collected from SIV-infected or recombinant glycoprotein-immunized monkeys were characterized for antibodies participating in antibody-complement-mediated cytolysis (ACC) and antibody-dependent cellular cytolysis (ADCC) in terms of their IgG subclass and epitope specificity. In a competitive inhibition ELISA, gp110-specific antibody reactivity with nondenatured rgp110 was blocked completely by soluble homologous rgp110 and partially inhibited by heterologous rgp110, suggesting cross-reactivity between viral strains. However, only partial inhibition was observed with denatured recombinant gp140 (rgp140) in selected monkeys, indicating that the majority of gp110-specific antibodies recognized conformational epitopes. ACC activity against recombinant vaccinia-infected, envelope-expressing targets was found in sera from both infected and immunized monkeys, whereas ADCC activity was observed only in sera from infected monkeys. ACC was blocked with denatured rgp140 as well as nondenatured rgp110, indicating that ACC-mediating antibodies recognized mainly linear epitopes. In contrast, rgp140 did not compete as effectively as rgp110 in the ADCC assay, indicating that the majority of ADCC antibodies recognized conformational epitopes. Competitive inhibition using three peptide fragments of gp110 indicated that epitopes recognized by ACC antibodies lie within amino acid residues 214-471, a region that spans V3, whereas ADCC-reactive epitopes lie between amino acid residues 52 and 214 at the N-terminal end of gp110. Column chromatography of rhesus IgG resulted in three subclass-enriched fractions, designated IgG-I, IgG-II, and IgG-III. IgG-I, but not IgG-II or IgG-III, from both infected and immunized monkeys mediated ACC, whereas IgG-I and IgG-II from infected monkeys mediated ADCC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Squamous epithelial proliferative lesions associated with rhesus Epstein-Barr virus in simian immunodeficiency virus-infected rhesus monkeys.

Proliferative lesions were found on the squamous epithelium of the tongue, esophagus, or penis or haired skin of the lip, hand, or thorax of 8 simian immunodeficiency virus-infected rhesus monkeys that died of simian AIDS. The lesions were focal and consisted of hyperkeratosis, parakeratosis, and acanthosis in the skin, with additional ballooning degeneration in the tongue, esophagus, and penis. The epithelial surfaces were frequently colonized by Candida species or gram-positive cocci. Intranuclear inclusion bodies were seen in cells in the middle and superficial layers. Herpesvirus virions were found in inclusion-bearing cells by transmission electron microscopy. An Epstein-Barr-like virus was identified in inclusion-bearing cells by immunohistochemistry and in situ hybridization. No virus was detectable in basal layers of the epithelium. These lesions resemble oral hairy leukoplakia in AIDS patients and may thus provide a useful primate model to study permissive epithelial infection by Epstein-Barr-like viruses.

Animals↗
PubMed1995

Genotypic selection of simian immunodeficiency virus in macaque infants infected transplacentally.

To understand viral and host factors that contribute to transplacental transmission of human immunodeficiency virus, we developed an animal model using pregnant female macaques infected with simian immunodeficiency virus (SIV). Pregnant females were inoculated intravenously during midgestation with either a well-characterized primary isolate of SIV (SIV/DeltaB670) or a combination of SIV/DeltaB670 and the macrophage-tropic molecular clone SIV/17E-Fr. The viral genetic diversity in five infected female macaques and their in utero-infected infants was analyzed. All of the mothers harbored a genetically diverse virus population at parturition, whereas a single genotype from the maternal quasispecies was identified in the infants at birth. Only one of two variants was found in the infants: SIV/17E-Fr (two cases) or a genotype contained within the SIV/DeltaB670 quasispecies (three cases). The macrophage-tropic properties of both transmitted genotypes were suggested by productive replication in primary rhesus macrophage cultures in vitro and the clonal presence in central nervous system tissue of infected monkeys with encephalitis. These observations provide compelling evidence for both genotypic and phenotypic selection in transplacental transmission of SIV and suggest a critical role for macrophages in fetal infection in utero.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus.

The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIVmac239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.

Animals↗
PubMed1995

Experimental leprosy in monkeys. I. Sooty mangabey monkeys: transmission, susceptibility, clinical and pathological findings.

A total of 31 sooty mangabey monkeys (SMM) (Cercocebus torquatus atys) inoculated by various routes with differing numbers of SMM-origin Mycobacterium leprae (ML) and 4 SMM inoculated with human-origin ML were observed for 4-12 years. SMM-origin ML was more pathogenic in SMM than human-origin ML. The spectrum of disease ranged from indeterminate to borderline and lepromatous in different animals. Some animals developed pure neural leprosy. Erythema nodosum leprosum (SNL) was also observed. Combined intravenous/intracutaneous (IV/IC) routes of inoculation more effectively induced advancing, disseminated lepromatous forms of leprosy; IV or IC routes alone were less effective at comparable doses. Total IV/IC doses of SMM-origin ML equal to or greater than 5 x 10(8), with morphologic indices (MIs) ranging from 5 to 10%, produced advancing, disseminated LL leprosy in 92% of SMM. Lower IV/IC doses and inoculations by a single IV or IC route produced fewer leprosy infections and more spontaneous regressions. As a species, captive SMM are highly susceptible to experimental leprosy and provide an excellent model for the longitudinal study of leprosy.

Animals↗
PubMed1995

Experimental leprosy in monkeys. II. Longitudinal serological observations in sooty mangabey monkeys.

In this study, 11 SMM were grouped and inoculated with differing doses of SMM-origin Mycobacterium leprae (ML) between 4.5 x 10(8) and 1 x 10(9) by either combined IV/IC routes or by IV or IC route alone. The combined route was the most effective in eliciting progressive, disseminated LL leprosy. In all, 6 of 7 SMM inoculated by the combined routes developed leprosy requiring treatment at some point. Only 1 of 4 inoculated by a single route developed persisting leprosy requiring chemotherapy. Either no disease or spontaneous regression of initial disease occurred in the other 3 animals inoculated by a single route. Doses in excess of 1 x 10(9) ML were more effective than lesser doses. An association was observed between the development of IgG anti-PGL-I ELISA OD values and resistance to leprosy and between IgM anti-PGL-I and leprosy progression or susceptibility. Serum PGL-I antigen levels, determined by dot ELISA, paralleled disease severity longitudinally. High positive OD values of anti-LAM IgG prior to ML inoculation were observed in the majority of leprosy-susceptible SMM in contrast to negative levels in more resistant animals. Anti-LAM IgG OD values exceeded the positive cut-off point after inoculation in 5 of 11 SMM; 3 of these 5 had concurrent detectable serum levels of PGL-I antigen.

Animals↗
PubMed1994

Immune responses induced by prototype vaccines for AIDS in rhesus monkeys.

A battery of assay systems was used to profile both humoral and cell-mediated immune responses induced by immunization with candidate vaccines consisting of recombinant simian immunodeficiency virus (SIV) glycoproteins rgp110 (nondenatured) with SAF-M adjuvant (gp110 + SAF-M) or rgp140 (denatured) with Freund's adjuvant (gp140 + FA). All of the monkeys became infected after intravenous challenge. However, 16 days following infection, viral antigenemia was reduced in both groups of vaccinates compared to controls. After 23 days antigenemia in the gp110 + SAF-M group remained at the same level as on day 16, whereas antigenemia in the gp140 + FA group was significantly reduced further than the level observed on day 16. Both vaccines induced blastogenic responses in PBMC cultures stimulated with rgp140, which decreased after repeated immunizations. Both vaccines induced high ELISA titers of IgG antibody against rgp140 that were equivalent to the titers in asymptomatic long-term survivors (LTSs). gp110 +/- SAF-M induced high titers of neutralizing antibody. In contrast, gp140 + FA failed to induce neutralizing antibody, suggesting that the natural conformation of the antigen may be essential for the induction of neutralizing antibody. High titers of antibodies capable of complement-mediated cytolysis (ACC) were induced by gp110 + SAF-M, whereas minimal ACC antibodies were induced by gp140 + FA. In spite of high titers of antibodies by ELISA, neither gp110 + SAF-M nor gp140 + FA vaccines induced detectable levels of antibody capable of antibody dependent cell-mediated cytolysis (ADCC). Detectable amounts of MHC class I-restricted, CD8+ cytotoxic T lymphocytes (CTLs) were not induced in immunized monkeys before challenge. After challenge and infection, antibody responses to glycoprotein (detected by ELISA and ACC) as well as glycoprotein-specific CTLs were induced in gp140 + FA vaccinates at levels higher than in nonimmunized control animals, indicating a priming effect by gp140 + FA immunization. No priming effect for ADCC antibody induction was observed in monkeys vaccinated with either gp110 + SAF-M or gp140 + FA. Rhesus monkey groups immunized with two different SIV envelope vaccines differed regarding potentially protective humoral and cell-mediated immune responses. The physical state of the immunogens, the type of adjuvant used, and/or the immunization protocol apparently affected these responses in both a qualitative and quantitative manner.

AIDS Vaccines↗
PubMed1994

Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys.

U-75875 inhibits human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus (SIV) proteases and blocks Gag-Pol protein processing and viral maturation and replication in vitro. Rhesus monkeys were treated with vehicle alone or with formulated U-75875 at doses of 7 or 20 mg/kg of body weight per day for 26 days by continuous intravenous infusion beginning 6 h prior to intravenous inoculation with 10 monkey 50% infectious doses of SIV Delta B670, and the monkeys were monitored until death. The effects of treatment on the level of SIV p26 antigenemia, the infectious virus titer in serum, and the level of proviral DNA in blood mononuclear cells evaluated by PCR were assessed. SIV infection of the controls resulted in an initial viral antigenemia that began 5 to 10 days postinoculation (p.i.), reached peak values on days 10 to 14 p.i., and lasted for more than 15 days. Proviral DNA was detectable in peripheral blood mononuclear cells by 7 to 11 days p.i., reached the mean peak level by 11 days p.i., and remained at high levels through day 24 p.i. Infectious virus was detected in serum from all of the infected controls by 24 days p.i. Treatment with U-75875 for 26 days resulted in a dose-related delay in the day of the peak level of antigenemia (P = 0.034). The level of proviral DNA in peripheral blood mononuclear cells at 11 days p.i. was significantly decreased in a dose-related fashion in the treated monkeys ( P </- 0.048), with a delay in the attainment of the peak level of proviral DNA in the treated groups. The titer of infectious virus in the serum of the group treated with 20 mg/kg/day was significantly decreased on day 24 p.i. compared with that in the serum of controls ( P = 0.046). Treatment with formulated U-75875 was well tolerated in rhesus monkeys and resulted in an inhibitory effect of SIV in vivo.

Animals↗
PubMed1993

Events leading to septic death from experimental acute pyelonephritis in the monkey.

Experimental acute pyelonephritis in monkeys led to death in some of the animals following renal E. coli inoculation. It was found that both the inflammatory response and cytokine activation were much more severe in these monkeys as compared with others that survived. IL-1 was decreased just before death, and there were early increases in IL-2 and IL-6 serum concentrations, but no significant increase in TNF values. The data suggest that death in sepsis is due in part to excessive cytokine release because of a decrease in the protective activity of IL-1.

Acute Disease↗
PubMed1993

Neonatal disease induced by SIV infection of the rhesus monkey (Macaca mulatta).

Seven 72-hr-old Indian origin rhesus monkeys (Macaca mulatta) were inoculated with 10 animal ID50 of SIV/DeltaB670. Nine age-matched animals were used as uninoculated controls. All seven inoculated animals became infected as verified by viral isolation and SIV p26 antigenemia. Five of seven infected animals died within a mean of 31 days (range, 26-41 days), with high levels of antigenemia beginning 1-2 weeks postinoculation (PI) that persisted until death. Absolute lymphocyte numbers were within normal limits in all animals in both groups throughout the study. Inoculated animals that died within a mean of 31 days (short-term survivors) had significantly lower numbers of CD4+CD29+ (helper/inducer) lymphocytes than did long-term surviving inoculated animals through 3 weeks PI. Numbers of CD4+ lymphocytes were no different when controls were compared to all inoculated animals through 4-5 weeks PI. The two inoculated animals surviving 216 and 423 days PI (long-term survivors) did demonstrate declining CD4+ cells, but only late in disease. CD8+ lymphocytes were significantly lower in short-term survivors when compared to long-term survivors through 5 weeks PI. Antibody production against SIV viral proteins was detected only in the long-term survivors and was similar to results from past studies in juveniles. Clinical signs in the inoculated group were consistent with those seen in past studies on older animals. Persistent bacterial infections, primarily of the GI and respiratory tracts, were seen in the infected group. Aside from the lack of some opportunistic infections such as cytomegalovirus (CMV) and Pneumocystis carinii, necropsy findings were not different when compared to past studies on juvenile animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of initiation of 3'-azido,3'-deoxythymidine (zidovudine) treatment at different times after infection of rhesus monkeys with simian immunodeficiency virus.

The effects of initiating treatment with 3'-azido-3'-deoxythymidine (zidovudine) at different times after inoculation of simian immunodeficiency virus (SIV) were investigated in rhesus monkeys. Zidovudine treatments of 100 mg/kg/day (25 mg/kg, subcutaneously every 6 h) were initiated 1, 8, 24, or 72 h after intravenous inoculation of 10 ID50 of SIV. Treatments continued for 28 days, and results were compared with those of saline-treated controls. Serum infectious virus titers 14 days after inoculation (AI) significantly decreased after treatment initiation 1, 8, or 24 h AI. Titers were correlated with the time treatment was initiated. Treatments initiated 1-72 h AI prevented the establishment of persistent SIV antigenemia; greater effects were observed with earlier initiation of treatment. Treatments initiated 1-8 h AI resulted in decreased levels of viral antigenemia 14 days AI and delayed decreases in CD4+CD29+ blood lymphocytes. Earlier treatment initiation resulted in delayed recurrence of antigenemia, with a tendency for longer survival. Early initiation of treatment may be important for limiting initial viral replication and dissemination in cases of known exposure.

Animals↗
PubMed1993

Protective anti-idiotype antibodies in the primate model of pyelonephritis.

The adherence of P-fimbriated Escherichia coli to a receptor containing alpha-D-Gal-(1-4)-beta-D-Gal (Gal-Gal) on urothelial cells is an important pathogenic mechanism in the development of pyelonephritis. Antibodies (Ab1) that had been produced by immunization with Gal-Gal conjugated with bovine serum albumin were specifically purified and used to stimulate the production of anti-idiotypic antibodies (Ab2) in cynomolgus monkeys (Macaca fascicularis). While sera from all of the Ab2-producing monkeys contained antibodies reactive with Ab1 and P-fimbriae, not all of the sera inhibited P-fimbrial binding to the Gal-Gal receptor. On the basis of the inhibition of binding, Ab2-producing monkeys were divided into two groups, termed reactive and nonreactive. The reactive and nonreactive Ab2-producing monkeys, together with a group of control monkeys, were challenged with a renal inoculation with P-fimbriated Escherichia coli. Hematologic, immunologic, microbiologic, and pathologic data were compared among the three groups. The reactive monkeys, whose Ab2 in serum inhibited binding between P-fimbriae and the Gal-Gal receptor, were protected against renal damage compared with the control group. The nonreactive group shared some parameters with the reactive group but overall developed renal damage comparable to that of the controls.

Animals↗
PubMed1991

Efficacy of SIV/deltaB670 glycoprotein-enriched and glycoprotein-depleted subunit vaccines in protecting against infection and disease in rhesus monkeys.

Immunization with an inactivated whole-virus vaccine is highly effective in preventing lentivirus infection. The viral protein(s) essential to the induction of protective responses, however, have not been identified. To define the role of virion components in the induction of protective immunity, we evaluated the efficacy of glycoprotein-enriched and glycoprotein-depleted simian immunodeficiency virus (SIV) subunit vaccines prepared by lentil-lectin affinity chromatography of gradient-purified virions using the immunization and challenge regimen previously found successful with an inactivated whole-virus vaccine. Infection was determined by successful recovery of virus, the induction of SIV-specific antibody responses, and infection of naive recipients by inoculation with lymph-node-derived lymphocytes from the vaccinates. Immunization with the glycoprotein-enriched preparation prevented infection in two out of four monkeys, whereas the glycoprotein-depleted vaccine failed to prevent infection in all four vaccinates tested. However, the glycoprotein-depleted vaccine appeared to moderate the progression of SIV-induced disease compared with non-immunized infected control monkeys inoculated with the same challenge dose. These data suggest that subunit vaccines containing sufficient quantities of viral glycoproteins can protect against SIV infection, whereas subunit vaccines composed predominantly of viral core proteins cannot. The development of effective vaccines against HIV infection should include studies on the optimum presentation of the viral envelope glycoproteins to produce long-term broadly protective immune responses.

Animals↗
PubMed1991

Lentivirus-induced pulmonary lesions in rhesus monkeys (Macaca mulatta) infected with simian immunodeficiency virus.

Necropsy reports from 28 rhesus monkeys that had been experimentally infected with simian immunodeficiency virus (SIV) and that were free of cytomegalovirus were reviewed. Lung sections from 24 of these monkeys that had no etiologic agent other than SIV detected in the lung were studied in detail by histopathologic, immunohistochemical, and electron microscopic examination and by in situ hybridization. Fourteen of the monkeys were part of a serial euthanasia study, while others were euthanatized after they became moribund. The following lesions were detected: perivascular inflammation, vasculitis, interstitial pneumonia, syncytial cells, hemorrhage, fibrin exudation, and pleural fibrosis. Perivascular inflammation was the most frequent lesion and occurred as early as 2 weeks after inoculation. Severe pneumonia and numerous syncytial cells were seen only in animals euthanatized because they had become moribund. The lesions appeared to be directly due to SIV infection. SIV antigens, RNA, and virions were detected in syncytial cells and macrophages by immunohistochemical examination, in situ hybridization, and transmission electron microscopic examination, respectively. The amount of virus present was correlated with the severity of the lesions. The SIV-induced lesions were different from those of the lymphocytic interstitial pneumonia, which occurs in human immunodeficiency virus-infected children and in ovine lentivirus-infected sheep and goats.

Animals↗
PubMed1991

Arthritis in rhesus monkeys experimentally infected with simian immunodeficiency virus (SIV/DELTA).

The joint tissues from 36 rhesus (age 2-5 years) infected with SIV/Delta were graded into four groups and then correlated with the following systemic immunologic parameters: numbers of CD4+, CD4+ plus CD29+, and CD20+ cells and SIV/Delta antigenemia. Grade I (n = 16) consisted of normal synovial membrane; grade II (n = 8) consisted of synovial hyperplasia; grade III (n = 8) consisted of a mononuclear cell infiltrate, and grade IV (n = 4) consisted of synovial membrane infiltration of syncytial cell and mononuclear type cells. Synovial membranes from 20 uninfected age-matched rhesus were compared with infected animals and were graded 1. Immunostaining of the tissue phase lymphocytes and viral antigen was performed using monoclonal antibodies commercially available and a monoclonal antibody produced against a core protein of the SIV/Delta agent. SIV/Delta infection resulted in a reduction in cells doubly stained for CD4+ and CD29+ and a relative increase in CD8+ stained cells. A significant (ANOVA) difference was not observed in CD4+, CD4+ plus CD29+, CD8+, or CD20+ among the various grades of arthritis. Viral antigen was demonstrated in syncytial cells of the grade IV reaction. This finding suggests that the SIV/Delta arthritis is a primary viral reaction.

Animals↗
PubMed1991

Experimental borderline lepromatous leprosy with intraneural erythema nodosum leprosum in a mangabey monkey (Cercocebus atys).

A sooty mangabey monkey (Cercocebus atys) was inoculated with Mycobacterium leprae and developed borderline lepromatous leprosy and intraneural erythema nodosum leprosum. Previously studied mangabeys have developed only disseminated lepromatous leprosy without reactions. This case broadens the spectrum of leprosy seen in experimentally inoculated animals and further characterizes the nonhuman primate model of leprosy.

Animals↗