A Minimally Replicative HIV-2 Live-Virus Vaccine ProtectsM. nemestrinafrom Disease after HIV-2287Challenge

Abstract

M. nemestrina immunized with an apathogenic HIV-2 molecular clone (HIV-2KR) were protected from CD4 decline and disease upon challenge with HIV-2(287), after any immunizing virus could be detected. Higher but not lower inocula of HIV-2KR were protective against intravenous inoculation of either 10(5) or 10(1) TCID50 of HIV-2(287). Protected animals displayed substantial reductions in PBMC proviral burden (1-3 logs), viral titers (1-2 logs), and plasma viral RNA (2-4 logs) compared to unprotected or naive animals as early as 1 week postinfection. Plasma viral RNA became undetectable after 24 weeks in protected animals, but remained high in unprotected animals. No viral RNA was present in the spleen of the protected animal necropsied more than a year after challenge (though viral DNA was still present). No neutralizing responses could be demonstrated, but CTL activity was detected sooner and at higher levels after challenge in protected than in unprotected macaques. In this novel HIV-2 vaccine model, protection was clearly dose-dependent, and clearance of challenge virus RNA from the plasma did not require detectable ongoing replication of the immunizing virus at the time of challenge.

Rapid CD4+T-Cell Loss Induced by Human Immunodeficiency Virus Type 1NCin Uninfected and Previously Infected Chimpanzees

“…The destruction of CD4 ϩ T cells results in the development of severe immunodeficiency, which leads to the emergence of opportunistic infections and neoplasia, ultimately culminating in death (9). Despite the development of a number of animal models of pathogenic lentiviral infection, including simian immunodeficiency virus (SIV) (2,13,25) and HIV-2 infection of macaques (22,28), and the development of pathogenic HIV-SIV chimeric viruses (21,31), an animal model of pathogenic HIV-1 infection has not been developed.…”

Differences among nonhuman primates in susceptibility to bone marrow progenitor transduction with retrovirus vectors

“…For example, intervening therapies for HIV infection can only be assessed in species susceptible to infection with HIV or related viruses such as simian immunodeficiency virus (SIV). [16][17][18]41 Several large animal models have been used for the study of bone marrow transduction with retrovirus vectors. Models involving the use of beagles, 6,42 and swine, 7 offer the advantages of large size, ease of handling, and efficient breeding.…”

“…We also included in this comparison marrow from pigtailed macaques. We did this based on the use of this species in a wide array of biomedical research, including the study of HIV, [16][17][18] and methods of inducing HSC mobilization. 19 This comparison was carried out using widely employed transduction conditions, including the enrichment of marrow for CD34 + cells, the use of amphotropic pseudotyped MLV reporter vectors, and culture in virus supernatant supplemented with a combination of cytokines (IL-3, IL-6 and SCF) found to enhance efficient transduction of primitive hematopoietic elements in mice and humans.…”

“…Further, these results sugGene Therapy gest that the rate of gene transfer can be significantly increased by carrying out transduction cultures at 33°C on CH-296-coated dishes. This species is especially attractive as a nonhuman primate model due to its wide use in several areas of biomedical research, including HIV infection, [16][17][18] and the similarity of its HSC mobilization characteristics to those of other commonly used nonhuman primate species and humans. 19 There are several critical reagents available for this species, including cross-reactive cytokines, antibodies for a wide array of lymphohematopoietic lineages, 41 and a mAb for separating CD34 cells.…”

“…Further, a review of the literature revealed no previous bone marrow transduction studies with pigtailed macaques (M. nemestrina), although this species has been used extensively in other fields of biomedical research. [16][17][18][19] We found that CD34-enriched marrow progenitors from pigtailed macaques were transduced at about twice the rate as progenitors from the other three species of nonhuman primates and humans using standard culture conditions. Semiquantitative RT/PCR suggests this difference may be due to differences in expression of the amphotropic receptor Pit2 (previously known as Ram1), [20][21][22] providing further evidence for the role of receptor expression in the relative susceptibility to retrovirus vector transduction.…”