Insights into the Impact of CD8⁺Immune Modulation on Human Immunodeficiency Virus Evolutionary Dynamics in Distinct Anatomical Compartments by Using Simian Immunodeficiency Virus-Infected Macaque Models of AIDS Progression

Abstract

A thorough understanding of the role of human immunodeficiency virus (HIV) intrahost evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8 lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to clinical manifestations similar to those for HIV-1 infection and AIDS progression, as well as a characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8 lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8 cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques with or without CD8 lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8 lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intrahost evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were depleted of CD8 lymphocytes exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8 lymphocytes in prolonging disease progression through continual control of SIV subpopulations from various anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation. Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged the time to AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although it is difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuro-AIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressures, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host, with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

“…These studies were taken as strong, if not the main, evidence for an important effect of CD8+ cells in controlling the virus—and likely were one of the key aspects for the rational to develop CD8+ T‐cell‐based vaccines . Subsequent studies used this experimental approach to try to characterize in more detail the biology of HIV/SIV infection and the mechanisms of action of the CD8+ cells . For example, the contrasting results of depleting these cells in pathogenic models of SIV versus natural hosts of SIV, which do not develop overt disease, were analyzed in multiple studies …”

“…26 Subsequent studies used this experimental approach to try to characterize in more detail the biology of HIV/ SIV infection and the mechanisms of action of the CD8+ cells. [41][42][43][44][45][46][47] For example, the contrasting results of depleting these cells in pathogenic models of SIV versus natural hosts of SIV, which do not develop overt disease, were analyzed in multiple studies. [48][49][50][51] One of the most common uses of CD8+ cell depletion is to investigate the effects of vaccine protocols.…”

Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques

“…The SIVmac251 rhesus macaque model of HIV-1 infection and pathogenesis has been one of the most frequently used models to study HIV-1 viral pathogenesis, vaccine research, drug development, and eradication (27–34). The model recapitulates HIV-1 infection and progression to AIDS in humans as well as infection of myeloid cells in the CNS (35–37).…”

Virus dynamics and phyloanatomy: Merging population dynamic and phylogenetic approaches

“…Rather HIV and simian immunodeficiency virus (SIV) infections are characterized by sequential fixation of CTL escape mutations . Interestingly, this pattern of sequential fixation is broken by depleting CD8 + T cells in rhesus macaques without reducing the evolutionary rate or changing the degree of compartmentalization …”

“…35 We extended our recent simulation model, 95 47,48 Interestingly, this pattern of sequential fixation is broken by depleting CD8 + T cells in rhesus macaques without reducing the evolutionary rate or changing the degree of compartmentalization. 49 More recently, Feder et al 39 If the resistance mutation in the second compartment was still at low frequency, a compartmentalization test would be positive.…”