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There are several lines of evidence that CD8 T cells contribute to the control of HIV replication

There are several lines of evidence that CD8 T cells contribute to the control of HIV replication. Keywords: HIV, CD8 lymphocytes +, broadly neutralising antibodies, synergy, elite controllers, elite suppressors Introduction There are more than 37 million people worldwide infected with human immunodeficiency virus (HIV). Although access to antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality, it is not a cure. A vaccine or cure strategy is usually desperately needed to end the requirement for life-long ART. HIV contamination is characterized by high levels of plasma viremia that can be controlled, to varying degrees, by virus-specific immune responses. There are several lines of evidence that CD8 T cells contribute to the control of HIV replication. There is a temporal association between the emergence of HIV-specific CD8 T cells and the decline Igf1r of viremia in primary contamination (1, 2). There is an overrepresentation of certain Class I MHC alleles in patients known as elite suppressors (ES) or viremic controllers (VC) who control viral replication to low or undetectable levels without ART (3, 4). Many of these subjects have more potent HIV-specific CD8 T cell responses than patients known as chronic progressors (CP) who do not control viral replication without ART (4C8). Further, in the simian immunodeficiency virus (SIV) macaque model of HIV contamination, the depletion of CD8 lymphocytes leads to rebound of SIV viremia in animals that had previously controlled viremia (9). Additionally, the reappearance of SIV-specific CD8 T cells coincides with reestablishment of viral control (10). Therefore, it is clear that optimal CD8 T cell responses to HIV are essential for viral control. Broadly neutralizing antibodies (bNAbs) can also contribute to HIV control and have dual functionality; the variable regions neutralize the virus, whereas the constant domains can engage Fc receptors on effector cells of the immune system (11). The administration of bNAbs immediately after contamination has been shown to prevent contamination and seeding of the Brazilin latent HIV reservoir (12). Additionally, in human trials, CD4 binding-site (CD4bs) Abs have a transient effect on viral load in individuals who are not on ART, and administration of bNAbs during analytical treatment interruption (ATI) can delay rebound of the virus (13C15). The use of vaccines or other therapeutic strategies to boost immune responses to the virus may eventually lead to long term HIV remission. Therapeutic vaccines aim to either improve the functional capacity of the host CD8 response to kill infected CD4 T cells or increase the potency of circulating antibodies able to neutralize circulating viruses. Thus far, therapeutic vaccines have proven to be unsuccessful, as previous vaccine strategies have shown some induction of CD8 T cells or neutralizing antibodies, but they have not led to long term control of viral replication when ART is usually discontinued (16, 17). The challenges that have arisen in the development of such a vaccine suggest that a combinatorial approach may be necessary to harness both neutralizing antibodies and sub optimal CD8 T cell responses to suppress virus replication. The goal of our study was to develop an model that assessed whether suboptimal CD8 T cell responses and bNAb treatment function synergistically or independently to suppress HIV contamination. Thus, we designed experiments to interrogate how viral replication proceeds in the presence of CD8 T cells and bNAbs, separately or in combination. Our results have implications for HIV therapeutic and cure strategies. Methods Subjects Blood samples from HIV-negative and HIV-positive donors were obtained with written informed consent and subsequently handled in accordance with protocols approved by the Johns Hopkins University IRB. HIV controllers are Brazilin made up of two different classes of subjects. An elite suppressor (ES) refers to a subject who has maintained undetectable viral loads in the absence of ART (18). A viremic controller (VC) refers to a patient who has maintained viral loads below 1000 copies/ml in the absence of ART (19). NL4.3-Delta-Env-GFP X4 Virus A single round X4 tropic enveloped NL4-3 virus with GFP engineered into?env was generated as previously reported (20). In brief, NL4-3 delta env backbone and a separate X4 envelop plasmid were transfected into 293T cells using lipofectimine following manufacturers recommendations. Virus supernatants were collected 72h post transfection an ultracentrifuged to concentrate and purify virus. Virus was reconstituted in R10 ON Brazilin at 4.C.