In 2011, a total of 28,038 new HIV diagnoses were reported by European Union and European Economic Area countries. The annual rate of HIV diagnoses does not show clear signs of decrease and HIV continues to be concentrated in selected populations such as men who have sex with men and injecting drug users, and a high proportion reported as late presenters. Despite effective and available antiretroviral treatment, the number of AIDS cases increased in a few countries.
Eurosurveillance: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20329
The UN’s latest assessment of global cases of HIV/Aids shows there has been a further drop in new infections among children. There were 330,000 new infections in children last year – 24% lower than in 2009: http://bbc.in/105nt2P
I’m quite fond of Tat, the HIV protein which greatly enhances the efficiency of HIV transcription. I worked on trans-activation of human retrovirus genomes for quite a while, and made a little bit of progress, but back then the biochemical mechanisms involved in these processes were mysterious. We’ve learned a fair amount since my limited contribution, but there’s still plenty more to find out, which is why a new paper showing how Tat tinkers with the nucleolar proteome. And then?
Nucleolar Protein Trafficking in Response to HIV-1 Tat: Rewiring the Nucleolus. (2012) PLoS ONE 7(11): e48702. doi:10.1371/journal.pone.0048702
The trans-activator Tat protein is a viral regulatory protein essential for HIV-1 replication. Tat trafficks to the nucleoplasm and the nucleolus. The nucleolus, a highly dynamic and structured membrane-less sub-nuclear compartment, is the site of rRNA and ribosome biogenesis and is involved in numerous cellular functions including transcriptional regulation, cell cycle control and viral infection. Importantly, transient nucleolar trafficking of both Tat and HIV-1 viral transcripts are critical in HIV-1 replication, however, the role(s) of the nucleolus in HIV-1 replication remains unclear. To better understand how the interaction of Tat with the nucleolar machinery contributes to HIV-1 pathogenesis, we investigated the quantitative changes in the composition of the nucleolar proteome of Jurkat T-cells stably expressing HIV-1 Tat fused to a TAP tag. Using an organellar proteomic approach based on mass spectrometry, coupled with Stable Isotope Labelling in Cell culture (SILAC), we quantified 520 proteins, including 49 proteins showing significant changes in abundance in Jurkat T-cell nucleolus upon Tat expression. Numerous proteins exhibiting a fold change were well characterised Tat interactors and/or known to be critical for HIV-1 replication. This suggests that the spatial control and subcellular compartimentaliation of these cellular cofactors by Tat provide an additional layer of control for regulating cellular machinery involved in HIV-1 pathogenesis. Pathway analysis and network reconstruction revealed that Tat expression specifically resulted in the nucleolar enrichment of proteins collectively participating in ribosomal biogenesis, protein homeostasis, metabolic pathways including glycolytic, pentose phosphate, nucleotides and amino acids biosynthetic pathways, stress response, T-cell signaling pathways and genome integrity. We present here the first differential profiling of the nucleolar proteome of T-cells expressing HIV-1 Tat. We discuss how these proteins collectively participate in interconnected networks converging to adapt the nucleolus dynamic activities, which favor host biosynthetic activities and may contribute to create a cellular environment supporting robust HIV-1 production.
Human immunodeficienty virus (HIV) infection is suppressed but not eliminated by antiretroviral drugs. Viral persistence in the face of therapy has been explained by viral latency, lowered effectiveness of drugs in some anatomical sites and cell types, and cell-to-cell spread. These mechanisms allow for drug-sensitive virus to persist despite treatment. Understanding the persistence mechanism at work at different times after infection, including the time of initial infection immediately following transmission when reservoirs are first formed, will reveal if we are at the limit of what can be achieved with the current therapy paradigm of suppressing ongoing virus replication with drugs.
This short review discusses some of the possible reasons why HIV persists at different points on the infection timeline, focusing on the role ongoing replication may have in maintaining the infection despite drugs at early times postexposure.
In the absence of intervention, only about one third of infants born to HIV-1 infected mothers who are continuously exposed to maternal breast milk over prolonged periods get infected. This observation raises the possibility that immune factors in infected women play a role in limiting HIV-1 transmission. Identifying factors associated with reduced HIV-1 transmission risk will improve our understanding on the potential correlates of protection that should be the focus of generating effective immunogens and vaccination protocols.
Researchers assessed the functional role of breast milk antibodies in a group of women with high plasma viral loads and systemic neutralizing Abs and determined that overall, breast milk contains low levels of neutralizing antibodies when compared to plasma. In contrast, they observed a robust non-neutralizing activity in breast milk that was associated with infant infection status. This study adds to the growing evidence of a potential role of non-neutralizing antibodies in limiting HIV-1 transmission and calls for more attention to this arm of the HIV-1 response.
HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads. (2012) PLoS Pathog 8(6): e1002739. doi:10.1371/journal.ppat.1002739
There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman’s autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS) – only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log10 lower (compared to 0.59 log10 lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001)and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk.
It seems to be turning into nanotechnology week on MicrobiologyBytes :-)
Nanotechnology and the Treatment of HIV Infection. (2012) Viruses 2012, 4(4), 488-520; doi:10.3390/v4040488
Suboptimal adherence, toxicity, drug resistance and viral reservoirs make the lifelong treatment of HIV infection challenging. The emerging field of nanotechnology may play an important role in addressing these challenges by creating drugs that possess pharmacological advantages arising out of unique phenomena that occur at the “nano” scale. At these dimensions, particles have physicochemical properties that are distinct from those of bulk materials or single molecules or atoms. In this review, basic concepts and terms in nanotechnology are defined, and examples are provided of how nanopharmaceuticals such as nanocrystals, nanocapsules, nanoparticles, solid lipid nanoparticles, nanocarriers, micelles, liposomes and dendrimers have been investigated as potential anti-HIV therapies. Such drugs may, for example, be used to optimize the pharmacological characteristics of known antiretrovirals, deliver anti-HIV nucleic acids into infected cells or achieve targeted delivery of antivirals to the immune system, brain or latent reservoirs. Also, nanopharmaceuticals themselves may possess anti-HIV activity. However several hurdles remain, including toxicity, unwanted biological interactions and the difficulty and cost of large-scale synthesis of nanopharmaceuticals.
Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism.
HIV-1 has been analysed by structural biology techniques more than any other virus, with partial or complete structures known for all 15 of its protein components and additional structures determined for substrate- and host factor-bound complexes. Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions.
For almost 25 years, key components of the lentivirus HIV-1, including the envelope glycoproteins, the capsid and the replication enzymes reverse transcriptase, integrase and protease, have been scrutinized to near atomic-scale resolution. Moreover, structural analyses of the interactions between viral and host cell components have yielded key insights into the mechanisms of viral entry, chromosomal integration, transcription and egress from cells. This review article discusses recent advances in HIV-1 structural biology, focusing on the molecular mechanisms of viral replication and on the development of new therapeutics:
HIV-1 possesses a viral protein, integrase (IN), which is necessary for its efficient integration in target cells. However, it has been reported that an IN-defective HIV strain is still capable of integration. Here, we assessed the ability of wild type (WT) HIV-1 to establish infection in the presence of IN inhibitors. Researchers observed a low, yet clear infection of inhibitor-incubated cells infected with WT HIV which was identical to cells infected with IN-deficient HIV. The IN-independent integration could be enhanced by the pretreatment of cells with DNA-damaging agents suggesting that integration is mediated by a DNA repair system. Significantly faster viral replication kinetics with augmented viral DNA integration was observed after infection in irradiated cells treated with IN inhibitor compared to non-irradiated cells. These results suggest that HIV DNA has integration potential in the presence of an IN inhibitor and may serve as a virus reservoir.
In the absence of intervention, only about one third of infants born to HIV-1 infected mothers who are continuously exposed to maternal breast milk over prolonged periods get infected. This observation raises the possibility that immune factors in infected women play a role in limiting HIV-1 transmission. Identifying factors associated with reduced HIV-1 transmission risk will improve our understanding on the potential correlates of protection that should be the focus of generating effective immunogens and vaccination protocols.
