Interferon‐alpha, immune activation and immune dysfunction in treated HIV infection

112

188

Section: Discussionmentioning

confidence: 99%

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

Lavender¹,

Gibbert

Peterson³

et al. 2016

112

188

“…If these cells were derived from the tumor as a result of metastasis, this again would explain the ability of the virus to replicate despite cART, dispersal of virus among tissues, and evidence of rapid and recent expansion of a replicating viral population. Furthermore, cancers can induce type I IFN production, which may play a role in anti-tumor immunity (47), drive T cell dysfunction (48), and contribute to other aspects of HIV disease pathogenesis, for example, virus control (MX2 postentry inhibition [49], APOBEC3 restriction of replication [50], BST-2 virus release [51], and NK cell activation [52]) or immune activation or dysfunction (CD38 expression on CD8 ϩ T cells [53], CD4…”

Section: Discussionmentioning

confidence: 99%

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer

Rose¹,

Lamers²,

Nolan

et al. 2016

While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV ؉ cART-treated (cART ؉ ) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART ؉ and cARTnaive (cART ؊ ) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA ؉ cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. IMPORTANCECombined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV ؉ cART ؉ individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies.A lthough current combined antiretroviral therapy (cART) regimens can extend the lives of individuals infected with human immunodeficiency virus (HIV) by years or decades, two major problems remain. First, HIV is never eradicated in treated patients and plasma viral loads (VL) will rebound if treatment is stopped. Subsets of T cells (1-7) and lymph (8, 9) are considered likely reservoirs of virus during cART. Vi...

“…After more than 30 years of research, it is still unclear how HIV-1 infection leads to persistent immune activation and CD4 T cell depletion (1). Presumably, aberrant immune activation is a result of multiple factors that can contribute to the exhaustion and death of CD4 T cells in HIV-infected individuals.…”

mentioning

confidence: 99%

“…The role of IFN-I in HIV-1-induced immune activation is complex and is not entirely understood (1). HIV-1 infection rapidly induces high levels of IFN-I, which may exert a selective pressure on HIV-1, resulting in establishment of the systemic infection with relatively fit and IFN-resistant virus (6).…”

mentioning

confidence: 99%

HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms

Reszka-Blanco

Sivaraman

Zhang

et al. 2015

Plasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-␣). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-␣ production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-␣ in pDCs, which contributes to pathogenesis. IMPORTANCE Plasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear.We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-␣ production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings thus provide new insights into the mechanism by which HIV-1 induces IFN-␣ in pDCs and contributes to HIV-1 pathogenesis. These novel findings will be of great interest to those working on the roles of IFN and pDCs in HIV-1 pathogenesis in general and on the interaction of HIV-1 with pDCs in particular. HIV-1 infection is characterized by both chronic immune activation and severe CD4 T cell loss, eventually progressing to AIDS. After more than 30 years of research, it is still unclear how HIV-1 infection leads to persistent immune activation and CD4 T cell depletion (1). Presumably, aberrant immune activation is a result of multiple factors that can contribute to the exhaustion and death of CD4 T cells in HIV-infected individuals. The mechanisms that are proposed to explain HIV-1-related chronic immune activation include disruption of intestinal integrity and microbial translocation (2); caspase-1-medi...