Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm

Nilsson, Charlotta; Mäkitalo, Barbro; Thorstensson, Rigmor; Norley, Stephen; Binninger-Schinzel, Doris; Cranage, Martin; Rud, Erling W.; Biberfeld, Gunnel; Putkonen, Per

doi:10.1097/00002030-199817000-00006

Cited by 73 publications

(50 citation statements)

References 33 publications

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“…Although such live attenuated viruses can confer protection against a homologous virus challenge (11,14,25,36,57,64), they provide only partial protection against a heterologous virus infection (16,34,44,63). The results of the present study are consistent with those findings in that prior infection did not prevent superinfection with a heterologous virus, but did damp replication of the second virus at peak and in the post-acute phase of superinfection.…”

Section: Discussionmentioning

confidence: 99%

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Yeh

Jaru-Ampornpan

Nevidomskyte

et al. 2009

J Virol

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Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virus for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4 ؉ T-cell count, CD4 ؉ memory T-cell subsets, cytokine production by virus-specific CD8 ؉ or CD4 ؉ cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4؉ T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses.Superinfection with human immunodeficiency virus type 1 (HIV-1) is the infection of an HIV-seropositive individual with a second heterologous strain of the virus after infection with the first infecting strain is established. There is accruing evidence for HIV-1 intra-and intersubtype superinfection in settings of intravenous drug use, structured treatment interruptions, and with strains that are resistant to antiretroviral drugs (2,4,6,22,26,28,32,39,42,43,52,60,66). Epidemiologic studies have suggested that the frequency of superinfection ranges from rare to as high as 5% per year in high-risk populations (9,10,15,20,24,27,31,40,41,51,59,65,67). However, it remains unclear how readily superinfections occur after exposure of an infected individual to a heterologous strain of virus. Furthermore, the variables that may contribute to susceptibility or resistance to superinfection, such as the timing of exposure to a second virus or the immunologic status of the exposed individual, have not been well defined. It is also uncertain whether superinfection is invariably associated with the loss of HIV containment and clinical deterioration (8,17,21,23,26,27,30,60). Understanding the risks for and the biological consequences of HIV superinfection will not only clarify an important clinical problem, it may also provide important insig...

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Section: Discussionmentioning

confidence: 99%

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Yeh

Jaru-Ampornpan

Nevidomskyte

et al. 2009

J Virol

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“…Attenuated simian immunodeficiency virus (SIV) vaccines elicit reproducible, potent protection against detectable infection with wild-type virus challenge via mucosal (Cranage et al, 1997;Nilsson et al, 1998) and parenteral Daniel et al, 1992) routes. While live retrovirus-based vaccines raise profound safety concerns (Baba et al, 1995(Baba et al, , 1999, studies in macaques may lead to an understanding of how such vaccines operate.…”

Section: Introductionmentioning

confidence: 99%

Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8)

Berry

Stebbings

Ferguson

et al. 2008

Journal of General Virology

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Vaccination with live attenuated simian immunodeficiency virus (SIVmacC8) confers potent, reproducible protection against homologous wild-type virus challenge (SIVmacJ5). The ability of SIVmacC8 to confer resistance to superinfection with an uncloned ex vivo derivative of SIVmac251 (SIVmac32H/L28) was investigated. In naïve, Mauritian-derived cynomolgus macaques (Macaca fascicularis), SIVmac32H/L28 replicated to high peak titres (.10 8 SIV RNA copies ml), persisted at high levels and induced distinctive pathology in lymphoid tissues. In cynomolgus macaques vaccinated with SIVmacC8, no evidence of detectable superinfection was observed in 3/8 vaccinates following challenge 3 or 20 weeks later with SIVmac32H/L28. Analyses after SIVmac32H/L28 challenge revealed a significant reduction in viral RNA (P,0.001) and DNA levels between 20 week vaccinates and challenge controls. Amongst 3 week vaccinates, less potent protection was observed. However, analysis of env from breakthrough virus indicated .99 % sequence similarity with the vaccine virus. Highly sensitive PCR assays that distinguish vaccine and challenge virus stocks demonstrated restimulation of replication of the vaccine virus SIVmacC8 in the face of potent protection against a vigorous, homologous challenge virus. Vaccine-induced antiviral neutralizing antibodies and anti-Nef CD8 + cytotoxic T cell responses did not correlate with the outcome of the challenge. Defining the mechanism of vaccine protection will need to account for the effective control of a genetically closely related challenge virus whilst remaining unable to suppress replication of the pre-existing vaccine virus. The role of innate and intrinsic anti-retroviral immunity in the protection conferred by live attenuated SIV vaccines warrants careful study.

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“…Live attenuated SIV vaccines can confer effective protection against detectable superinfection with pathogenic, wild-type SIV (3,13,14,29,58,59) and SIV/HIV-1 chimeric virus (7,18,46). Yet there are limits to the breadth of this protection, and live attenuated SIV vaccines have failed to protect against certain heterologous challenge viruses or failed to protect against a challenge performed several years postinoculation (22,31,58). Furthermore, the demonstrated potential for reversion to pathogenicity in live attenuated SIV precludes clinical evaluation of a live attenuated HIV vaccine (6,38,39,57).…”

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confidence: 99%

CD8 ⁺ Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

Stebbings¹,

Berry²,

Waldmann

et al. 2005

J Virol

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In order to test the hypothesis that CD8 ؉ cytotoxic T lymphocytes mediate protection against acute superinfection, we depleted >99% of CD8 ؉ lymphocytes in live attenuated simian immunodeficiency virus macC8 (SIVmacC8) vaccinees from the onset of vaccination, maintained that depletion for 20 days, and then challenged with pathogenic, wild-type SIVmacJ5. Vaccinees received 5 mg per kg of humanized anti-CD8 monoclonal antibody (MAb) 1 h before inoculation, followed by the same dose again on days 3, 7, 10, 13, and 17. On day 13, peripheral CD8 ؉ T lymphocytes were >99% depleted in three out of four anti-CD8 MAb-treated vaccinees. At this time attenuated SIVmacC8 viral RNA loads in anti-CD8 MAb-treated vaccinees were significantly higher than control vaccinees treated contemporaneously with nonspecific human immunoglobulin. Lymphoid tissue CD8 ؉ T lymphocyte depletion was >99% in three out of four anti-CD8 MAb-treated vaccinees on the day of wild-type SIVmacJ5 challenge. All four control vaccinees and three out of four anti-CD8 MAb-treated vaccinees were protected against detectable superinfection with wild-type SIVmacJ5. Although superinfection with wild-type SIVmacJ5 was detected at postmortem in a single anti-CD8 MAb-treated vaccinee, this did not correlate with the degree of preceding CD8 ؉ T lymphocyte depletion. Clearance of attenuated SIVmacC8 viremia coincided with recovery of normal CD8 ؉ T lymphocyte counts between days 48 and 76. These results support the view that cytotoxic T lymphocytes are important for host-mediated control of SIV primary viremia but do not indicate a central role in protection against acute superinfection conferred by inoculation with live attenuated SIV.

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Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm

Abstract: The live attenuated SIVmacC8 vaccine was able to induce long-term protection against heterologous intrarectal SIVsm challenge in a proportion of macaques but not against the more divergent HIV-2, which was given intravenously.

Cited by 73 publications

References 33 publications

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8)

CD8 ⁺ Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

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Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm

Abstract: The live attenuated SIVmacC8 vaccine was able to induce long-term protection against heterologous intrarectal SIVsm challenge in a proportion of macaques but not against the more divergent HIV-2, which was given intravenously.

Cited by 73 publications

References 33 publications

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8)

CD8 + Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

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CD8 ⁺ Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus