Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Gandhi, Rajesh T.; McMahon, Deborah; Bosch, Ronald J.; Lalama, Christina M.; Cyktor, Joshua C.; Macatangay, Bernard; Rinaldo, Charles R.; Riddler, Sharon A.; Hogg, Evelyn; Godfrey, Catherine; Collier, Ann C.; Eron, Joseph J.; Mellors, John W.; Team, Actg A Study

doi:10.1371/journal.ppat.1006285

Cited by 161 publications

(158 citation statements)

References 48 publications

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“…By contrast, in CSFV persistently infected pigs, that showed high and constant viral load, we found a lower CD4/CD8 ratio with respect to naïve or CSFV antibody positive pigs. This finding is in agreement with studies in persistent infection in humans, where the low CD4/CD8 ratio correlated with high viral load and an inability of the immune system to clear the virus (Gandhi et al., ). Also, it has been established that during HIV persistent infection, the T‐cell functions including cytokine secretion and proliferative capacity appear to decrease gradually, being associated with the immune exhaustion phenomenon (Khaitan & Unutmaz, ).…”

Section: Discussionsupporting

confidence: 92%

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Low CD4/CD8 ratio in classical swine fever postnatal persistent infection generated at 3 weeks after birth

Bohórquez

Wang

Pérez‐Simó

et al. 2018

Transbound Emerg Dis

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Classical swine fever virus (CSFV) is one of the most important pathogens affecting swine. After infection with a moderate virulence strain at 8 hours after birth, CSFV is able to induce viral persistence. These animals may appear clinically healthy or showed unspecific clinical signs despite the permanent viremia and high viral shedding, in absence of immune response to the virus. Given the role played by this infection in disease control, we aimed to evaluate the capacity of CSFV to induce postnatal persistent infection at 3 weeks after birth. Nine pigs were CSFV infected and sampled weekly during 6 weeks and viral, clinical, pathological and immunological tests were carried out. Also, the CD4/CD8 ratio was calculated with the purpose to relate this marker with the CSFV persistent infection. The IFN‐α response was detected mainly 1 week after infection, being similar in all the infected animals. However, 44.4% of animals were CSFV persistently infected, 33.3% died and 22.2% developed specific antibody response. Interestingly, in persistently infected pigs, the T‐CD8 population was increased, the T‐CD4 subset was decreased and lower CD4/CD8 ratios were detected. This is the first report of CSFV capacity to confer postnatal persistent infection in pigs infected at 3 weeks after birth, an age in which the weaning could be carried out in some swine production systems. This type of infected animals shed high amounts of virus and are difficult to evaluate from the clinical and anatomopathological point of view. Therefore, the detection of this type of infection and its elimination in endemic areas will be relevant for global CSF eradication. Finally, the low CD4/CD8 ratios found in persistently infected animals may be implicated in maintaining high CSFV replication during persistence and further studies will be performed to decipher the role of these cells in CSFV immunopathogenesis.

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Section: Discussionsupporting

confidence: 92%

“…Lower CD4/CD8 ratios have been detected in humans suffering persistent and chronic infections with HIV and hepatitis C virus (HCV) (Dustin, 2017). In this regard, a lower CD4/CD8 ratio has also been found in patients with persistently higher HIV-1 viral load (Gandhi et al, 2017).…”

mentioning

confidence: 99%

Low CD4/CD8 ratio in classical swine fever postnatal persistent infection generated at 3 weeks after birth

Bohórquez

Wang

Pérez‐Simó

et al. 2018

Transbound Emerg Dis

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“…Based on our findings, CMV replication should be considered in future studies dissecting the relationship between HIV reservoir size and immune activation. For example, in a recent longitudinal study of long-term virally suppressed PLWH, correlations between HIV reservoir size and T cell activation were not detected (32). However, immune activation associated with subclinical CMV replication may have confounded the results.…”

Section: Discussionmentioning

confidence: 98%

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy

Christensen-Quick

Massanella

Frick

et al. 2019

J Virol

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Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR ϩ CD38 ϩ ), cycling (Ki-67 ϩ ), degranulation (CD107a ϩ ), and the immune checkpoint protein PD-1 on CD4 ϩ and CD8 ϩ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4 ϩ T cell activation and CD107a expression and with increased CD8 ϩ T cellular cycling and reduced CD107a expression on CD8 ϩ T cells. While some effects disappeared during ART, greater CD4 ϩ T cell activation and reduced CD107a expression on CD8 ϩ T cells persisted when CMV was present (P Ͻ 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4 ϩ T cell activation was higher and CD8 ϩ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4 ϩ T cells are more vulnerable to HIV infection, while the loss of CD8 ϩ T cell degranulation may impede the proper killing of infected cells.

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“…During HIV-1 infection, persistent immune activation and inflammation are driven by multiple factors, including residual virus replication, inflammatory lipids, gut microbial translocation, and coinfection [92][93][94]. Although long-term effective ART substantially reduces the level of immune activation and inflammation in HIV-1-infected individuals, it fails to normalize the activation and inflammation [95][96][97][98][99]. It was reported that persistent T-cell activation was associated with decreased CD4 + T-cell gains in HIV-1-infected individuals during ART 53.…”

mentioning

confidence: 99%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

212

214

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Cited by 161 publications

References 48 publications

Low CD4/CD8 ratio in classical swine fever postnatal persistent infection generated at 3 weeks after birth

Low CD4/CD8 ratio in classical swine fever postnatal persistent infection generated at 3 weeks after birth

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

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