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Development of virus-specific immune responses in SHIV(KU)-infected macaques treated with PMPA
1Marion Merrell Dow Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, Kansas, 66160, USA. akumar@kumc.edu
Abstract:
Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to the suppression of HIV viremia below the threshold of detection for several years. However, impact of HAART on reconstitution of virus-specific immune responses remains poorly understood. In this study, four macaques were infected with pathogenic SHIV(KU). One week postinoculation two of the four animals were treated with PMPA [9-R-(2-phosphophomethoxypropyl)adenine] daily for 83 days. Two other macaques, that did not receive treatment, exhibited explosive virus replication accompanied by a near total loss of CD4(+) T cells and succumbed to AIDS-related complications within 6 months of infection. These animals did not develop any virus-specific immune responses. On the contrary, the animals that received PMPA showed transient loss of CD4(+) T cells that recovered during the treatment period. The virus burden declined below the level of detection that rebounded soon after cessation of PMPA therapy. The virus replicated productively for several weeks before both animals controlled the productive replication of virus. This control of virus replication was found to be associated with the development of virus-specific neutralizing antibodies, T-helper cells, and CTLs. Although PMPA did not eliminate virus from the animals, it provided them with enough time to mount virus-specific immune responses that eventually controlled the virus replication in the blood. Our results suggest that antiretroviral therapy, if initiated early during infection, would help the host in mounting virus-specific immune responses that might control productive replication of the virus.
Insights
Early antiretroviral therapy (ART) in macaques infected with SHIV suppressed viral load, allowing for the development of virus-specific immune responses. This immune reconstitution eventually controlled viral replication, suggesting ART aids the host in fighting HIV.
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Highly active antiretroviral therapy (HAART) suppresses HIV viremia but its effect on virus-specific immune responses is unclear.
- Understanding immune reconstitution is crucial for optimizing HIV treatment strategies.
Purpose of the Study:
- To investigate the impact of early antiretroviral intervention on immune responses in a pathogenic SHIV infection model.
- To determine if early treatment facilitates the development of adaptive immunity against the virus.
Main Methods:
- Four macaques were infected with pathogenic SHIV(KU).
- Two macaques received daily PMPA [9-R-(2-phosphophomethoxypropyl)adenine] treatment for 83 days, starting one week post-inoculation.
- Control macaques did not receive treatment; viral load, CD4(+) T cell counts, and virus-specific immune responses (neutralizing antibodies, T-helper cells, CTLs) were monitored.
Main Results:
- Untreated macaques experienced rapid viral replication, CD4(+) T cell loss, and succumbed to AIDS-related complications without developing specific immune responses.
- PMPA-treated macaques showed transient CD4(+) T cell loss with recovery during treatment, and viral load suppression.
- Viral rebound occurred after PMPA cessation, but treated animals subsequently controlled virus replication through the development of neutralizing antibodies, T-helper cells, and CTLs.
Conclusions:
- Early initiation of antiretroviral therapy, even if not curative, can enable the host immune system to develop responses that control viral replication.
- Antiretroviral therapy provides a critical window for immune reconstitution, potentially leading to long-term control of persistent viral infections like HIV.