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1.  Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection 
The widespread access to antiretroviral treatment during the past decades has transformed HIV infection from a lethal disease to a chronic condition, in which the relative burden of non-AIDS-related chronic disorders such as cardiovascular disease, malignancy, renal, liver, and bone disease has increased. The adjusted relative risk for myocardial infarction is reported to be around 2-fold compared to that of the general population, which over time is likely to translate into increased absolute risk in an aging population. Thus, delineating potentially HIV-specific pathogenetic mechanisms is crucial in order to tailor novel strategies for prophylaxis and treatment. This review will focus on advances in the field that possibly link HIV-induced alterations of the gut mucosa and consequent microbial translocation to cardiometabolic risk factors in HIV infection. Recent work suggests that markers of microbial translocation are closely associated with several cardiovascular risk factors such as dyslipidemia, insulin resistance, hypertension, coagulation abnormalities, endothelial dysfunction, and carotid atherosclerosis. Future studies should investigate whether associations between microbial translocation and cardiovascular risk factors will translate into increased risk of acute events, and whether strategies to target gut microbiota and microbial translocation might reduce such a risk.
PMCID: PMC4046217  PMID: 24521167
2.  The High Cost of Fidelity 
The notoriously low fidelity of HIV-1 replication is largely responsible for the virus's rapid mutation rate, facilitating escape from immune or drug control. The error-prone activity of the viral reverse transcriptase (RT) is predicted to be the most influential mechanism for generating mutations. The low fidelity of RT has been successfully exploited by nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs) that halt viral replication upon incorporation. Consequently, drug-resistant strains have arisen in which the viral RT has an increased fidelity of replication, thus reducing analogue incorporation. Higher fidelity, however, impacts on viral fitness. The appearance of compensatory mutations in combination with higher fidelity NRTI resistance mutations and the subsequent reversion of NRTI-resistant mutations upon cessation of antiretroviral treatment lend support to the notion that higher fidelity exacts a fitness cost. Potential mechanisms for reduced viral fitness are a smaller pool of mutant strains available to respond to immune or drug pressure, slower rates of replication, and a limitation to the dNTP tropism of the virus. Unraveling the relationship between replication fidelity and fitness should lead to a greater understanding of the evolution and control of HIV.
PMCID: PMC3887412  PMID: 24180375
3.  Virological and Immunological Response to Antiretroviral Regimens Containing Maraviroc in HIV Type 1-Infected Patients in Clinical Practice: Role of Different Tropism Testing Results and of Concomitant Treatments 
We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatment-experienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA <50 copies/ml and immunological response as time to a CD4 cell count increase of ≥100/μl from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log10 higher: HR 1.29, 95% CI 1.05–1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96–4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.
PMCID: PMC3887413  PMID: 23971941
4.  Monoclonal Antibody-Based Candidate Therapeutics Against HIV Type 1 
Treatment of HIV-1 infection has been highly successful with small molecule drugs. However, resistance still develops. In addition, long-term use can lead to toxicity with unpredictable effects on health. Finally, current drugs do not lead to HIV-1 eradication. The presence of the virus leads to chronic inflammation, which can result in increased morbidity and mortality after prolonged periods of infection. Monoclonal antibodies (mAbs) have been highly successful during the past two decades for therapy of many diseases, primarily cancers and immune disorders. They are relatively safe, especially human mAbs that have evolved in humans at high concentrations to fight diseases and long-term use may not lead to toxicities. Several broadly neutralizing mAbs (bnmAbs) against HIV-1 can protect animals but are not effective when used for therapy of an established infection. We have hypothesized that HIV-1 has evolved strategies to effectively escape neutralization by full-size antibodies in natural infections but not by smaller antibody fragments. Therefore, a promising direction of research is to discover and exploit antibody fragments as potential candidate therapeutics against HIV-1. Here we review several bnmAbs and engineered antibody domains (eAds), their in vitro and in vivo antiviral efficacy, mechanisms used by HIV-1 to escape them, and strategies that could be effective to develop more powerful mAb-based HIV-1 therapeutics.
PMCID: PMC3332369  PMID: 21827278
5.  Retroviral Coinfections: HIV and HTLV: Taking Stock of More Than a Quarter Century of Research 
Retroviral coinfections with HIV-1 and HTLV-1 or with HIV-1 and HTLV-2 occur with variable frequencies throughout the world with the highest prevalence in large metropolitan areas in the Americas, Europe, and Africa. The recognition that retroviral coinfections exist dates back to the discovery of HIV-1 over 25 years ago. Despite the large body of published information regarding the biological and clinical significance of retroviral coinfections, controversy throughout several decades of research was fueled by several flawed epidemiologic studies and anecdotal reports that were not always supported with ample statistical and scientific evidence. However, the growing consensus obtained from recent systematic and well-devised research provides support for at least three conclusions: (1) HIV-1 and HTLV-1 coinfections are often seen in the context of patients with high CD4+ T cell counts presenting with lymphoma or neurological complications; (2) HIV-1 and HTLV-2 coinfections have been linked in some cases to a “long term nonprogressor” phenotype; and (3) differential function and/or overexpression of the HTLV-1 and HTLV-2 Tax proteins likely play a pivotal role in the clinical and immunologic manifestations of HIV/HTLV-1 and -2 coinfections. This review will recount the chronology of work regarding retroviral coinfections from 1983 through the present.
PMCID: PMC3275926  PMID: 22171689
6.  cAMP During HIV Infection: Friend or Foe? 
Intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) are important regulators of immune cells, partially determining the balance between activation and suppression. In this review, we discuss the mechanisms by which HIV infection increases cAMP levels in T cells, as well as the effect of cAMP on HIV-specific responses and its effect on HIV replication and infection. Results suggest that increased cAMP levels during HIV infection may have a dual and opposite roles. On the one hand, they could have a protective effect by limiting viral replication in infected cells and decreasing viral entry. On the other hand, they could have a detrimental role by reducing HIV-specific antiviral immune responses, thus reducing the clearance of the virus and contributing to T cell dysfunction. Future studies are thus needed to further define the beneficial versus detrimental roles of cAMP, as they could help establish new therapeutic targets to combat HIV replication and/or identify novel ways to boost antiviral immune responses.
PMCID: PMC3251837  PMID: 21916808
7.  How Can HIV-Type-1-Env Immunogenicity Be Improved to Facilitate Antibody-Based Vaccine Development? 
No vaccine candidate has induced antibodies (Abs) that efficiently neutralize multiple primary isolates of HIV-1. Preexisting high titers of neutralizing antibodies (NAbs) are essential, because the virus establishes infection before anamnestic responses could take effect. HIV-1 infection elicits Abs against Env, Gag, and other viral proteins, but of these only a subset of the anti-Env Abs can neutralize the virus. Whereas the corresponding proteins from other viruses form the basis of successful vaccines, multiple large doses of HIV-1 Env elicit low, transient titers of Abs that are not protective in humans. The inaccessibility of neutralization epitopes hinders NAb induction, but Env may also subvert the immune response by interacting with receptors on T cells, B cells, monocytes, macrophages, and dendritic cells. Here, we discuss evidence from immunizations of different species with various modified Env constructs. We also suggest how the divergent Ab responses to Gag and Env during infection may reflect differences in B cell regulation. Drawing on these analyses, we outline strategies for improving Env as a component of a vaccine aimed at inducing strong and sustained NAb responses.
PMCID: PMC3251839  PMID: 21495876
8.  HIV Type 1 Gag as a Target for Antiviral Therapy 
The Gag proteins of HIV-1 are central players in virus particle assembly, release, and maturation, and also function in the establishment of a productive infection. Despite their importance throughout the replication cycle, there are currently no approved antiretroviral therapies that target the Gag precursor protein or any of the mature Gag proteins. Recent progress in understanding the structural and cell biology of HIV-1 Gag function has revealed a number of potential Gag-related targets for possible therapeutic intervention. In this review, we summarize our current understanding of HIV-1 Gag and suggest some approaches for the development of novel antiretroviral agents that target Gag.
PMCID: PMC3251841  PMID: 21848364
9.  Eradication Therapies for HIV Infection: Time to Begin Again 
Despite the success of antiretroviral therapy (ART) in decreasing mortality for HIV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing eradication of HIV infection. We will briefly review what is known about the mechanisms that establish and maintain persistent HIV infection despite ART, to create a framework in which to consider approaches to the clearance or eradication of infection (“cure”), or to allow clinical stability in the absence of ART (“functional cure”). With regard to eradication therapies, it could be said that as a field our position is analogous to that of ART early in the HIV pandemic. As then we must now simultaneously develop and optimize platforms and paradigms for the discovery and testing of eradication therapies, and begin to advance candidate therapies toward human testing.
PMCID: PMC3065332  PMID: 21314240
10.  Recent Insights into the Mechanism and Consequences of TRIM5α Retroviral Restriction 
The cellular factor TRIM5α inhibits infection by numerous retroviruses in a species-specific manner. The TRIM5α protein from rhesus macaques (rhTRIM5α) restricts infection by HIV-1 while human TRIM5α (huTRIM5α) restricts infection by murine leukemia virus (MLV). In owl monkeys a related protein TRIM-Cyp restricts HIV-1 infection. Several models have been proposed for retroviral restriction by TRIM5 proteins (TRIM5α and TRIM-Cyp). These models collectively suggest that TRIM5 proteins mediate restriction by directly binding to specific determinants in the viral capsid. Through their ability to self-associate TRIM5 proteins compartmentalize the viral capsid core and mediate its abortive disassembly via a poorly understood mechanism that is sensitive to proteasome inhibitors. In this review, we discuss TRIM5-mediated restriction in detail. We also discuss how polymorphisms within human and rhesus macaque populations have been demonstrated to affect disease progression of immunodeficiency viruses in these species.
PMCID: PMC3048830  PMID: 21247355
11.  Mechanisms for Env Glycoprotein Acquisition by Retroviruses 
A mandatory step in the formation of an infectious retroviral particle is the acquisition of its envelope glycoprotein (Env). This step invariably occurs by Env positioning itself in the host membrane at the location of viral budding and being incorporated along with the host membrane into the viral particle. In some ways, this step of the viral life cycle would appear to be imprecise. There is no specific sequence in Env or in the retroviral structural protein, Gag, that is inherently required for the production of an infectious Env-containing particle. Additionally, Env-defective proviruses can efficiently produce infectious particles with any of a number of foreign retroviral Env glycoproteins or even glycoproteins from unrelated viral families, a process termed pseudotyping. However, mounting evidence suggests that Env incorporation is neither passive nor random. Rather, several redundant mechanisms appear to contribute to the carefully controlled process of Env acquisition, many of which are apparently used by a wide variety of enveloped viruses. This review presents and discusses the evidence for these different mechanisms contributing to incorporation.
PMCID: PMC3048835  PMID: 21247353
12.  Appreciating HIV Type 1 Diversity: Subtype Differences in Env 
Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of intersubtype diversity. Recent studies have revealed that some of the HIV-1 subtypes exhibit phenotypic differences stemming from subtle changes in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtype differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most globally prevalent subtype.
PMCID: PMC2853864  PMID: 19327047

Results 1-12 (12)