HIV-1 Reservoir Formation in the Context of Pre-Antiretroviral Therapy Infection 公开
Brooks, Kelsie (Fall 2019)
Abstract
While antiretroviral therapy (ART) has changed the landscape of the HIV-1 epidemic, reducing mortality and providing an effective means of preventing infections, it fails to cure HIV-1 infection. ART drugs do not target the reservoir, a persistent population of latently infected cells that remain even with suppression of virus to undetectable levels in the blood.
Here we investigate the establishment of the reservoir in the context of the natural history of HIV-1 infection, sampling virus from seroconversion through chronic infection just before ART initiation, and assess the relationship between reservoir proviral variants and pre-therapy virus. In 13 Zambian individuals, we observed that although the majority of proviral variants in the reservoir are most closely related to virus present shortly before the initiation of treatment, provirus most closely related to very early infection virus is present in five of 13 individuals as well. In two individuals, we detected provirus matching the transmitted/founder (TF) virus, indicating persistence of the variant for over six years of ART-naïve infection in one case. Reservoir proviral variants were also significantly more closely related to the TF virus than virus in the blood just prior to the start of therapy, highlighting the contributions of earlier variants to the reservoir population. Sequential sampling of four individuals at two time points during ART indicated a yet shorter distance from the TF virus with continued time on treatment, or an enrichment in early infection variants.
Taken together, we conclude that these observations indicate the reservoir is seeded throughout ART-naïve infection, and that HIV-1 cure strategies designed to reduce or eliminate the reservoir must account for the presence of virus archived at all stages of the infection.
Table of Contents
Abstract
Acknowledgements
Chapter I: Introduction..................................................................................................1
Current Status of the Epidemic and Impetus for Further Research...................................1
HIV Acquisition: the Transmission Bottleneck and Features of Acute Infection...............4
Chronic Infection: Immune System Dysfunction...............................................................8
Chronic Infection: Evolution of the Quasispecies.............................................................11
The Reservoir: an Enigma.................................................................................................12 Summary...........................................................................................................................17
Chapter II: HIV-1 variants are archived throughout infection and persist in the
reservoir...........................................................................................................................18
Table 1...............................................................................................................................37
Figure 1..............................................................................................................................38
Figure 2..............................................................................................................................39
Figure 3..............................................................................................................................41
Figure 4..............................................................................................................................43
Figure 5..............................................................................................................................45
Figure 6..............................................................................................................................46
Figure 7...............................................................................................................................48
Supplemental Table 1.........................................................................................................49
Supplemental Figure 1........................................................................................................50
Supplemental Figure 2........................................................................................................52
Supplemental Figure 3........................................................................................................60
Chapter III: Discussion.....................................................................................................70
Connections to Infection Dynamics and Future Directions.................................................70
Significance for the Field and Implications for HIV Cure....................................................74
Summary..............................................................................................................................75 References............................................................................................................................76
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