Research Paper On HIV-Exposed Seronegative Immune Quiescence

Literature Review

Introduction
Discussion of the existing literature on the preventions of Human Immunodeficiency Virus (HIV), find cases of HIV-exposed seronegative individuals frequently considered representative models of novel prevention efforts. Reference to individuals demonstrating innate natural resistance to HIV infection identify as HIV-exposed seronegative (HESN) [1]. Despite the advances in the study of management of HESN of the HIV infection, none of the associations related with resistance to HIV infection including multiple genetic and immune factors account for all cases of HIV-exposed seronegativity [2].
Paul McLaren and his colleagues write of their findings of the potential mechanisms of resistance to HIV infection in the highly HIV-exposed seronegative commercial sex workers (CSWs) from Nairobi, Kenya [3]. Their 2010 article, “HIV-Exposed Seronegative Commercial Sex Workers Show a Quiescent Phenotype in the CD4+ T Cell Compartment and Reduced Expression of HIV-Dependent Host Factors,” McLaren and his colleagues concludes that phenomenon of lower baseline immune activation termed by them as “immune quiescence” may contribute to the host resistance to HIV [3]. Thus, the role of the immune quiescence in resistance and susceptibility to HIV infection in HESNs represent a novel mechanism of HIV prevention [4]. In this review, evidence based literature provides how immune activation emerges as a key dependency factor required for efficient HIV replication. As a result of the literature review, other research evidence supports the following proposed model of the immune quiescence as a mechanism for protection against HIV infection.

HIV Infection and Transmission

Literature, according to Al-Jabri shows the huge evidence suggesting there exists natural resistance to HIV infection in particular humans countering the subsequent progression to the acquired immunodeficiency syndrome (AIDS). [5 & 6] At the same time, as intended in this review the accurate biological mechanism accounting for this resistance continue lacking understanding. [5 & 6] Ongoing research looks for disclosure of the concise biological structures facilitating this natural resistance. At the same time this continued research focus may also reveal the development of appropriate therapeutic vaccines and other interventions. [5] Consequently, since non-progression as a long-term factor attributed with resistance to viral infections like HIV, the gaps in the literature supports the rarity of the phenomenon. [5 & 6] Further, with adequate control of factors contributing to rapid development into AIDS as a variable the delay of the onset of the symptomology therefore gives opportunity for better lifestyle to afflicted patients. [5] Nonetheless, current status for the majority of HIV infected globally, the only effective manner for controlling the HIV infection remains antiretroviral therapy [5]

HIV Adjunct to Immune Activation

Immune activation aligned to HIV replication connection remains a critical aspect of this process [7, 8, & 9] and literature shows the importance of immune activation as a major factor with destruction of rapid HIB disease progression and immune response [8]. At the same time, the connection between the susceptibility to HIV disease and immune activation continues lacking definitive causal factors. [4] Current in vitro research [10 & 11] exhibit results showing the quiescent cells susceptible to infection by HIV while at the same time with inefficient viral replication [12]. Consequently, the HIV specifically reveals infection occurring in activated T cells. [13] A reason this specificity emerges remains linked with the considerable number of required host factors creating efficient HIV duplication [14] as exhibited primarily in activated T cells. The assessment of this, therefore, reasonably hypothesizes those individuals showing lower immune activation levels ergo, would hypothetically have lower susceptibility to the HIV disease. Other data support earlier studies showing reduction of susceptibility to infection in the unstimulated HIV-exposed seronegative (HESN) as compared to controls. [15]

Role of Immune activation in HIV Transmission Models

Literature of outcomes of cooperative functional studies along with clinical trials testing microbicide applicable candidates proved vital for studying causal factors of the transmission of HIV. Since the earlier microbicide candidates proved ineffective preventing HIV – with some connected to the increased rates of HIV transmission [16] resulted in looking for more promising candidates. A promising microbicide contender proved a gel comprised of 1% tenofovir demonstrating a 39% after testing in the Centre for the Aids Programme of Research in South Africa (CAPRISA) 004 trial. [17] The scope of the immunity activation before exposure connected directly the risk increase for HIV seroconversion. [18] Regardless of either the use of placebo or microbicide this remains a risk factor. [18] The study concluded the value of considering suppression of activating innate immunities in the development of future antiretroviral HIV microbicides. [18]

HESN Exposure to the HIV Infection

Gender and HESN
Science knows not all people exposed to HIV necessarily contract the infection with some people exhibiting natural resistance to the disease and categorized as HESN representative of the novelty as a mode of preventive research efforts by scientists. Female sex workers provide a particular opportunity for study activation in HIV exposed HESNs. [19 -23] While identification of several protective correlates in a variety of HESN groups emerged nonetheless there remains no single cause accounting for all existing cases to date with resistance to the HIV disease. [19-32]

Quiescence and the T cell Immune

Evaluation of the T cell role activation in connection with resistance to infection in research literature showed phenotype T cells negative in HESN and HIV while susceptible. [23 -24] Other evidence of the T cell activation in HESN research participants registered low according to female participants in the studies. [3] As a result, analysis showed how unstimulated CD4+ cells in HESN subjects registered lower level gene expression than in the high risk HIV-negative study controls. [3] This suggested the existence of a quiescent cellular condition. [3] Further, T cell receptor signals with genetic involvement along with accommodating factors needed in replication of the HIV disease remained a part of those HSN under expressed genes. [3] In addition, identified HESN unstimulated cells secreted lower levels of cytokines ex vivo as compared to the study control groups.[3] Nonetheless, following the stimulation, the difference measured in the cytokine secretion remained unobservable. [3] Subsequently, this indicated HESN subjects with low level baseline cellular activation yet are not immunosuppressed even though responding to normally to stimulation. [22]

Regulatory T cells (Tregs) Drivers of immune quiescence

Tregs having the capacity for suppressing cellular activation puts the roll of these T cells in maintaining quiescence in the gender related study discussed above. [24] Tregs use multiple mechanisms that frame its ability for suppressing T cell activation as well as Tregs suppress T cell activation and responses through multiple mechanisms occurring indirectly through the interactions with dendritic cells (DC) or production of anti-inflammatory cytokines. [27] Directly the Tregs suppress the T cell activation and responses through the direct link with CD8+ T and CD4+ cells [27]. This suggests protection against HIV infection occurs by limiting the activation of predictable CD4+ T cells [27].

Contradictions in the Evidence

Conflicting data to the immune quiescence hypothesis shows in the literature reporting elevated immune activation linked with protection in HESN subjects. These T cell elevation levels from both activation and cytokine production as found in the systematic or the mucosal tests among the HESN sampling of injection drug users (IDU) [28] as well as the uninfected partners of identified HIV diseased people. [28] The analysis of other findings where the HESN IDU subject showed CD8+ and NK T cell compartment activation occurring at the same time subsequently measured reduced levels of CD4+ CCR5+ T cell targets suggesting the opportunity for certain subjects that CD4+ T cell quiescence occurring alongside the activation of other subsets of immune cells.

Protection/Prevention Immune Quiescence Models

The vital aspect of any consideration when translating the immune quiescence (IQ) hypothesis as a protective, preventative, and intervention to the HIV infection the model suggesting prompting the HIV exposure site with immune quiescence reduces the amount of target cells activated and consequently prevents infection or to a limitation of a smaller foci of the infected resting targeted cells. This allows clearing innate mechanisms or the mucosal HIV-specific T cells. [17] A practical method of inducing immune quiescence in the mucosa may be a microbicide that incorporates anti-inflammatory mediators into the formulation, perhaps in combination with antiretroviral compounds that have shown moderate efficacy in recent trials [14].
Employing such an approach frames around literature reporting research results of functional studies conducted after the CAPRISA 004 trial. [29] As a result the appropriate chemical compounds are drugs already approved by the FDA, proven ability reducing the onset of excessive immune activation, maintain consistent safety records, and remain affordable for developing countries. Numerous anti-inflammatory compounds prove potentially promising including type I interferon blockers [30], statin inhibitors [31], cyclooxygenase type 2 inhibitors [30], and chloroquine [31] addressing some if not all of the necessary requirements.
Review of the potential advantage of inducing the IQ phenotype approach considers the how it targets the hosting immune system and not the HIV disease. In doing so this inhibits any preponderance for the HIV mutating in response as an evasive measure to the chemical mechanism it encounters. Implementation of immune quiescence induction intended as a strategic reduction of the transmission of the HIV disease, nonetheless requires caution ensuring limitation of any excessive mucosal T cell activation occurs in connection to the response of the mucosal immune process. The importance of recalling how the IQ induction does not equate to the anergy induction. People with higher levels of T cells remain capable of reacting to mitogens or to recall antigens. [3]
The outcome of the gender related studies show the female HESN with a quiescent phenotype [3[and immunity specific to HIV. [3] As a result, the specific immunity to HIV in context to the decreased generalized T cell immune quiescence remains highly implausible although observed. Consequently those potential formulations targeting inducing IQ remain needing tested for having the ability reducing immune inflammation and activation while not interfering with HIV-specific innate antiviral mechanisms as exemplified by NK cells or CD8+ T cell responses.

Conclusion

Discourse from the above literature review about the research evidence indeed supports the proposed model of the immune quiescence as a mechanism for protection against HIV infection. The literature discussed numerous examples showing pre-existence of immune activation in research subjects prior to exposure to HIV as a risk factor for contract the HIV disease. The IQ model discussed therefore, suggests according to the literature on the HESN research provides implications supporting the ability of the IQ model reducing immune activation as a means providing viable protection against the HIV infection. The implications of the literature findings suggest this occurs with the limitation of pooling on the activation of the target CD4+ T cells with their susceptibility to the HIV infection
Existing differences in antiproteases and Tregs may prod the IQ phenotype. As a consequence future research ideally focuses on the manner of inducing immune quiescence combined with alternative strategies including HIV vaccines as well as microbicides. The IQ model discussed in the above literature review connection to the HESN characteristics for preventions of HIV referencing the HESN study samples remains an invaluable framework for the future success of research identifying the still enigmatic conditions creating these individuals’ resistance to HIV infection including multiple genetic and immune factors accounting for all cases of HIV-exposed seronegativity.

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