Infection of cynomolgus monkeys with HIV-2 protects against pathogenic consequences of a subsequent simian immunodeficiency virus infection

Simian immunodeficiency virus (SIV) infection in cynomolgus macaques leads to severe immunodeficiency with a fatal outcome. In contrast, HIV-2 infects these primates without apparently causing any immunological abnormalities. In this study three cynomolgus monkeys were experimentally infected with HIV-2 strain SBL-K135 and 168 days later challenged with 10-100 animal infectious doses of the closely related SIV strain SM to study protective immunity. At the time of SIV challenge the HIV-2-infected monkeys had neutralizing antibodies against HIV-2, but virus could no longer be recovered from their peripheral blood mononuclear cells (PBMCs) and no clinical symptoms or decrease in CD4+ lymphocytes were observed. Follow-up for 9 months after challenge with SIV showed that the HIV-2-infected monkeys were protected against SIV-induced immunodeficiency (no decrease of CD4+ lymphocytes) and lymphadenopathy. However, they were not resistant to SIV infection since virus could be recovered from their PBMCs and they developed anamnestic antibody responses. Four naive control monkeys which were inoculated with the same dose of SIV became persistently infected and developed a decrease of the absolute numbers of CD4+ cells and showed a marked lymphadenopathy. Two out of four control animals died 58-265 days postinfection with an immunosuppressive disease. Immunohistochemical examination showed abundant viral antigen in lymph-node biopsies from the SIV-infected control monkeys but absence of SIV or HIV-2 antigens in the biopsies from the three HIV-2-preinfected and SIV-superinfected monkeys. The present study demonstrates possibilities for induction of immunity against immunodeficiency induced by a primate lentivirus, a concept with application also to HIV infection and AIDS in man.     

Lack of protection against HIV-1 infection among women with HIV-2 infection.

OBJECTIVE: To assess whether HIV-2 infection protects against HIV-1 infection by comparing the rate of HIV-1 seroconversion among HIV-negative and HIV-2-seropositive women followed in a cohort study in Abidjan, C?te d'Ivoire. DESIGN: Prospective cohort study METHODS: HIV seroconversion was assessed in 266 HIV-seronegative, 129 HIV-1-seropositive, and 127 HIV-2-seropositive women participating in a closed cohort study of mother-to-child transmission of HIV conducted during 1990-1994. Participants were seen every 6 months, and blood samples were obtained. All blood samples were screened for HIV antibodies by enzyme immunoassay (EIA) and confirmed by line immunoassay (LIA) and Western blot. Among women who were HIV-seronegative at enrolment, seroconversion was defined as new EIA-reactivity confirmed on LIA and Western blot. Among HIV-1- or HIV-2-seropositive women, seroconversion to dual reactivity was defined as new dual reactivity on the LIA that was confirmed by reactivity on both HIV-1- and HIV-2-monospecific EIA. RESULTS: Five HIV-seronegative women became HIV-1-seropositive [seroconversion rate, 1.1 per 100 person-years; 95% confidence interval (CI), 0.3-2.5), and none became HIV-2-seropositive. No HIV-1-seropositive women became HIV-1/2 dually reactive, whereas six HIV-2-seropositive women acquired HIV-1 seroreactivity and thus became HIV-1/2 dually reactive (seroconversion rate 2.9 per 100 person-years; 95% CI, 1.1-6.3). HIV-2-seropositive women were more likely to acquire HIV-1 seroreactivity than were HIV-seronegative women (rate ratio, 2.7; 95% CI, 0.7-11.2), but this difference was not statistically significant (P>0.15). CONCLUSION: HIV-2 infection does not appear to protect against HIV-1 infection.     

Prevention of HIV-2 and SIVSM infection in cynomolgus monkeys by active or passive immunization.

We have established experimental infection with HIV-2 and SIVsm in cynomolgus monkeys and successfully used these models for vaccine experiments. Protection against homologous HIV-2 infection was demonstrated in two of two monkeys immunized with a Triton-X100-treated whole HIV-2SBL-6669 vaccine in incomplete Freund's adjuvant and in 2 of 4 monkeys immunized with a formalin-inactivated whole HIV-2 vaccine in RIBI adjuvant. Monkeys preinfected with a live poorly replicating HIV-2 strain were shown to develop cross-protection against SIV-induced disease. We have shown also that HIV-2 and SIVsm infection in cynomolgus monkeys can be prevented by passive immunization. These results raise hope for effective immunization against HIV infections in humans.     

Vaccine protection against simian immunodeficiency virus infection.

Rhesus monkeys were immunized by multiple inoculations with purified, disrupted, noninfectious simian immunodeficiency virus (SIV) in adjuvant. Immunized monkeys developed anti-SIV antibodies detectable by whole-virus ELISA and by immunoblot reactivity; these antibodies had weak neutralizing activity. One week after the last immunization, monkeys were challenged with 200-1000 animal infectious doses of uncloned, live SIV. The same strain of SIV that was used for vaccination was also used for challenge. Anamnestic antibody responses and SIV recovery from peripheral blood were used to evaluate infection following the live virus challenge; two of six vaccinated monkeys showed no evidence of infection following the live virus challenge. Transfusion of 10 ml of whole blood from these two into uninfected, naive rhesus monkeys did not result infection of the recipients, providing further support for the lack of infection in the two previously vaccinated animals. Four of four unvaccinated control monkeys inoculated with these doses of live SIV became infected and three of these died with AIDS 118-258 days after infection. Only one of the six vaccinated monkeys has died to date. In situ hybridization with lymph node biopsy specimens suggested that the virus load was much higher in control macaques than in vaccinated macaques. These results indicate that vaccination with inactivated whole virus can protect macaques against challenge with live SIV. Furthermore, they provide hope that vaccine protection against human AIDS virus infection may be possible.     

Trends and interaction of HIV-1 and HIV-2 in Guinea-Bissau, west Africa: no protection of HIV-2 against HIV-1 infection.

OBJECTIVES: To study trends in the prevalence and incidence of HIV-1 and HIV-2 infections in Guinea-Bissau over the last 7 years, and to evaluate the protective effect of HIV-2 against HIV-1 infection. DESIGN: Prospective follow-up of a cohort of police officers in Guinea-Bissau, and sentinel surveillance of pregnant women in Bissau. METHODS: Participants in the police cohort were tested regularly for antibodies to HIV and Treponema pallidum, and information about sexual risk behaviour and a history of sexually transmitted diseases was obtained. Simultaneously, pregnant women at the maternity wards at the National Hospital in Bissau were screened annually for HIV antibodies. To evaluate changes in prevalence and incidence of HIV in the police cohort, the study period was divided into three time strata with 2-3 years in each stratum. For the evaluation of a protective effect of HIV-2 on subsequent HIV-1 infection, two multivariate Poisson regression models were constructed, adjusting for different selected confounding variables. RESULTS: Between 1990 and 1997, 2637 police officers were included in the cohort study, 90.7% of whom were male. The overall prevalence of HIV-1 was 0.9%, of HIV-2 it was 9.7% and of HIV-1 and HIV-2 dual reactivity it was 0.5%. For pregnant women the prevalence rates were 0.9, 5.5 and 0.2% for HIV-1, HIV-2 and dual reactivity respectively. The prevalence of HIV-1 increased significantly whereas the prevalence of HIV-2 declined significantly during the study period, among both police officers and pregnant women. The total incidence of HIV-1 and HIV-2 was 0.74 and 0.83 per 100 person-years respectively in the police cohort. The incidence of HIV-1 increased slightly from 0.62 to 0.78 per 100 person-years (not significant), whereas the incidence of HIV-2 declined significantly from 0.90 to 0.35 per 100 person-years over the study period. Seven police officers seroconverted from HIV-2 to dual reactivity (1.22 per 100 person-years). The adjusted incidence ratio of acquiring HIV-1 infection among HIV-2-positive subjects compared with HIV-negative subjects was 1.65 [95% confidence interval (CI), 0.73-3.74] and 1.98 (95% CI, 0.80-4.87), depending on the confounding variables included. CONCLUSIONS: Our study shows an increasing prevalence of HIV-1 and a decreasing prevalence of HIV-2 in Guinea-Bissau. The incidence of HIV-2 declined significantly whereas the incidence of HIV-1 was relatively stable over the study period. No protective effect of HIV-2 against subsequent HIV-1 infection was observed, instead HIV-2-positive subjects had a tendency towards higher risk of acquiring HIV-1 infection compared with seronegative subjects.     

Chlamydial infection of subcutaneous fimbrial transplants in cynomolgus and rhesus monkeys

Acute infection with Chlamydia trachomatis serotype E was established in monkey fallopian tube fimbriae by subcutaneous implantation. Depending upon monkey species, from eight to 20 implants could be established in each animal. Animals were given estrogen before percutaneous inoculation of the autografts with Chlamydia. Acute inflammatory changes were found in homografts examined in the first week after infection, with chronic inflammatory changes noted thereafter. Chlamydial inclusions were detected within fimbrial epithelial cells up to seven days postinoculation by fluorescent-antibody staining and immunoperoxidase staining with C. trachomatis-specific monoclonal antibody. Organisms were recovered from autografts up to five days after infection. Analysis of serum antibody by microimmunofluorescence revealed that serotype E-specific antibody of both IgM and IgG classes was produced after infection. We conclude that subcutaneously implanted fallopian tube autografts may provide a useful primate model for kinetic studies of chlamydial infection and immunity.     

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Streptozotocin (STZ) is used to induce diabetes in experimental animals. It has a variety of adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renal failure, and metabolic acidosis. STZ also has effects on the immune system, being associated with lymphopenia in rodents, the mechanism of which is not fully understood. We present data on a significant STZ-associated reduction in lymphocyte count in nonhuman primates. We report a significant reduction in absolute lymphocyte count; in 2 monkeys, the lymphopenia persisted for >100 d. However, a significant increase in absolute monocyte count was noted. Furthermore, an increase in serum monocyte chemoattractant protein-1 (MCP-1) was observed. The reduction in lymphocyte numbers may contribute to immunomodulation that may be beneficial to a subsequent islet graft, and may reduce the need for immunosuppressive therapy. The increase in monocytes and MCP-1, however, may be detrimental to the islet graft. Studies are warranted to explore the mechanism by which STZ has its effect.     

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Streptozotocin (STZ) is used to induce diabetes in experimental animals. It has a varietyof adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renalfailure, and metabolic acidosis. STZ also has effects on the immune system, beingassociated with lymphopenia in rodents, the mechanism of which is not fully understood. Wepresent data on a significant STZ-associated reduction in lymphocyte count in nonhumanprimates. We report a significant reduction in absolute lymphocyte count; in 2 monkeys,the lymphopenia persisted for >100 d. However, a significant increase in absolutemonocyte count was noted. Furthermore, an increase in serum monocyte chemoattractantprotein-1 (MCP-1) was observed. The reduction in lymphocyte numbers may contribute toimmunomodulation that may be beneficial to a subsequent islet graft, and may reduce theneed for immunosuppressive therapy. The increase in monocytes and MCP-1, however, may bedetrimental to the islet graft. Studies are warranted to explore the mechanism by whichSTZ has its effect.     

DNA vaccination against hepatitis E virus infection in cynomolgus macaques

Background : The feasibility of DNA vaccination against hepatitis E in non‐human primates has not been evaluated. In the present study a full‐length hepatitis E virus (HEV) open reading frame (ORF)2 (Burmese strain) was assembled, cloned, and used for genetic immunization of cynomolgus macaques (cynos), which were subsequently challenged with a heterologous HEV strain (Mexico). Methods : Four cynos were vaccinated intramuscularly with the HEV ORF2 DNA cassette and one animal was vaccinated with a mock DNA construct. Results : Following vaccination anti‐HEV antibodies were detected in the four HEV‐DNA‐vaccinated cynos, but not in the control animal. When challenged, two of the four HEV‐DNA‐vaccinated cynos were protected against HEV infection and had no elevated alanine aminotransferase activity, viremia, or fecal shedding. The two other DNA‐vaccinated animals developed HEV infection and disease. Conclusion : These findings demonstrate the feasibility of DNA vaccination for the protection of HEV infection and warrant further studies to explore routes other than intramuscular for induction of a stronger and efficacious immune response. © 2002 Blackwell Publishing Asia Pty Ltd     

HIV-2 does not protect against HIV-1 infection in a rural community in Guinea-Bissau.

OBJECTIVE: To examine the putative protective effect of HIV-2 infection against subsequent HIV-1 infection. DESIGN: Retrospective analysis of data from two cross-sectional surveys in the same community. METHODS: Two surveys between 1989 and 1998 in a rural area in northwestern Guinea-Bissau provided data from residents aged 15-59 years. HIV testing was done in the first survey. In the second survey, tests were made for both HIV and syphilis, and data on sociodemographic factors and sexual behaviour, including commercial sex work, were gathered. Qualitative polymerase chain reaction amplification of HIV-1 and HIV-2 viral DNA was performed on serologically dually reactive samples. RESULTS: Of the 2276 eligible adult villagers initially tested, 60% (1360) provided a second sample. Of 110 HIV-2-infected subjects, 17 became additionally infected with HIV-1 [incidence rate (IR), 26.3/1000 person-years observation]. Of the 1250 HIV-seronegative subjects, 24 became infected with HIV-1 (IR, 2.8/1000 person-years observation). The incidence rate ratio (IRR), comparing the incidence rate in HIV-2-infected people with the rate in HIV-seronegative subjects, was > 1 in all three "risk groups": men, female commercial sex workers, and other women. The overall estimate of the IRR, adjusted for age group and risk group, was 3.24 (confidence interval, 1.5-7.1). CONCLUSIONS: There was no protective effect of HIV-2 in this population. HIV-2 cannot be regarded as a vaccine, but, instead, may be a risk factor for HIV-1 infection.     

Virus-specific cytotoxic T-lymphocytes in HIV-2-infected cynomolgus macaques.

OBJECTIVE: Specific cytotoxic T-lymphocytes (CTL) are induced in humans or monkeys after infection with HIV-1 or SIVmac, respectively. Since, like HIV-1, HIV-2 causes AIDS, our objective was to determine the characteristics of the HIV-2-specific CTL response. DESIGN: Since it is rarely possible to study cellular immunity in individuals, because of the small number of HIV-2-infected patients available in Europe and the necessity for co-operation in the performance of sequential CTL assays, cynomolgus macaques were infected with HIV-2. Autologous transformed B-lymphoblastoid cell lines infected with recombinant vaccinia viruses were used as target cells for cytotoxicity assays. METHODS: Recombinant vaccinia viruses expressing HIV-2 genes were constructed to infect B-lymphoblastoid cell lines from macaques. These cells were used as target cells for cytotoxicity assays with peripheral blood mononuclear cells from HIV-2BEN-infected cynomolgus macaques. To characterize the effector cells, CD8+ cells were separated with immunomagnetic beads. Major histocompatibility complex (MHC) restriction of the cytotoxic cells was determined by incubation with matched or mismatched target cells. RESULTS: HIV-2BEN-infected cynomolgus macaques raised CTL against proteins of the three major viral structural genes, gag, pol and env. The cytotoxic cells were CD8+ and their activity was MHC class I-restricted. In contrast to SIVmac-infected macaques, env-specific lysis was mediated exclusively by CD8+ cells. CTL from individual animals recognized different viral proteins and the recognition pattern varied over time. CONCLUSIONS: Like HIV-1 and SIVmac, HIV-2 induces virus-specific CTL. The variation of antigen recognition between individual animals and over time indicates that sequential experiments are necessary to determine the complete spectrum of the CTL response of infected animals. HIV-2-infected macaques represent a suitable model for investigations into the cellular immune response against HIV.     

Antibody-mediated protection against respiratory viral infection

Effective antibody responses are critical for protection against many human pathogens, including those with tropism for the respiratory tract (RT). Systemic immunoglobulin (Ig)G responses as well as mucosal IgA responses play complementary roles in protection against RT infections, and induction of a tissue-specific, isotype-appropriate humoral response is central to successful vaccination strategies. For respiratory virus infections in which current vaccines are either not available or not fully effective, antibody-mediated therapies may provide a viable treatment option. Prophylactic administration of polyclonal or monoclonal antibodies shows the best clinical efficacy, whereas therapeutic administration of antibodies after infection can also be highly protective but is greatly dependent on timing; efficacy declines soon after onset of disease symptoms. Further understanding of the mechanisms underlying antibody-mediated protection against respiratory virus infections may lead to improved immunization strategies as well as more effective antibody-based therapeutics.     

Prolonged survival of porcine hepatocytes in cynomolgus monkeys

BACKGROUND & AIMS: Management of patients with liver failure can be a significant medical challenge, and transplantation of the liver is the only definitive therapy. Whole liver allotransplantation is limited by a shortage of human donors and the risks of the surgery in those most ill. Transplants consisting of xenogeneic hepatocytes might overcome these problems, and work in rodents indicates that such transplants can correct some metabolic deficiencies and can prevent the complications and mortality associated with hepatic failure. As a prelude to clinical application, we tested the feasibility of hepatocyte xenotransplantation in nonhuman primates. METHODS: One to 2 billion hepatocytes from outbred swine were transplanted into the spleens of cynomolgus monkeys using conventional immunosuppression to control rejection. Duration of graft function was determined based on assay for porcine albumin. RESULTS: Following a single infusion, xenogeneic hepatocytes functioned for more than 80 days and, following re-transplantation, for more than 253 days. Engraftment in the spleen was confirmed 40 days after transplantation by asialoglycoprotein receptor-directed nuclear scanning. The humoral immune response to the transplanted porcine cells had no discernible impact on the survival of the grafts. CONCLUSIONS: Xenotransplantation of hepatocytes should be explored as a readily available, minimally invasive form of therapy for hepatic failure.     

Prior SARS-CoV-2 infection is associated with protection against symptomatic reinfection

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HIV-2 infection in an American

HIV-2 is endemic in West Africa but rare elsewhere. In the USA there have been 18 reported cases of HIV-2 infection; most identified people have been West Africans. We recently diagnosed the first case of HIV-2 infection in a native-born US citizen, a woman whose serum was found to be reactive to anti-HIV-1 enzyme immunoassay (EIA) when she attempted to donate blood in 1986. Although both HIV-1- and HIV-2-specific EIAs were reactive, the anti-HIV-2 Western blot (WB) was positive, while the anti-HIV-1 WB was positive or indeterminate on different occasions. Synthetic peptide testing was reactive for HIV-2 but not HIV-1. HIV-2 DNA was detected using the polymerase chain reaction procedure. Although she had travelled to West Africa, it is unclear how she became infected with HIV-2.     

HIV-2 infection in Denmark.

A collection of 3019 selected serum samples (ss), comprising 329 ss from intravenous drug abusers, 558 ss from homosexual men, 682 samples from persons attending a STD clinic, 100 ss from individuals of African origin, 300 ss from sexual contacts to Africans, 650 ss from Danish blood donors who resided in Africa greater than 2 years prior to donating the ss, and 400 ss with equivocal antibody reactions in an HIV-1 Western blot was tested for antibodies against HIV-2 by in-house HIV-2 ELISA and Western blot. Four ss were positive for antibodies against HIV-2. Three of the ss originated from West African men, the fourth belonged to the spouse of one of these men. Three of the samples presented with an uncharacteristic reaction in a HIV-1 Western blot. The study indicates that HIV-2 infection is not yet widespread in Denmark and that it remains closely related to West Africa.