The evolution of HIV-1 entry phenotypes as a guide to changing target cells

Through a twist of fate the most common form of HIV-1, as defined by entry phenotype, was not appreciated until recently. The entry phenotype is closely linked to the target cell and thus to virus–host interactions and pathogenesis. The most abundant form of HIV-1 uses CCR5 as the coreceptor and requires a high density of CD4 for efficient entry, defining its target cell as the CD4+ memory T cell. This is the transmitted form of the virus, the form that is found in the blood, and the form that rebounds from the latent reservoir. When CD4+/CCR5+ T cells become limiting the virus evolves to use alternative target cells to support viral replication. In the CNS, the virus can evolve to use a cell that displays only a low density of CD4, while maintaining the use of CCR5 as the coreceptor. When this evolutionary variant evolves, it must be sustaining its replication in either macrophages or microglial cells, which display only a low density of CD4 relative to that on T cells. In the blood and lymphoid system, the major switch late in disease is from T cells expressing CD4 and CCR5 to T cells expressing CD4 and CXCR4, with a change in coreceptor specificity. Thus the virus responds in two different ways to different environments when its preferred target cell becomes limiting. ©2018 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc

Reply to Sheward et al.: Two sampling issues in using Primer IDs

[No abstract available

The terminal redundancy of the retrovirus genome facilitates chain elongation by reverse transcriptase

Transcription of DNA from the RNA genome of retroviruses by reverse transcriptase involves an unusual translocation of the growing chain from the 5' end to the 3' end of the RNA template. In order to elucidate the mechanism by which this translocation occurs, we have used chain termination to analyze nascent viral DNA synthesized in vitro by avian sarcoma virus, and we have determined the nucleotide sequence of appropriate regions of viral DNA isolated from infected cells and cloned into prokaryotic vectors. Our results provide direct experimental evidence for a previously proposed model in which a short terminal redundancy in viral RNA, and a DNA copy of the redundant sequence, are used to allow the growing DNA chain to move from the 5' to the 3' end of the template. Transcription of avian sarcoma virus RNA with purified reverse transcriptase also generates an anomalous product, a hairpin DNA that arises when the initial DNA transcript folds back on itself to continue synthesis. The foldback is mediated by an inverted repeat of 5 nucleotides in the sequence of nascent DNA. Anomalous hairpin DNA is not produced by detergent-activated virions. Thus, constituents of the virons or the configuration of encapsidated viral RNA must faciliatate correct transcription

The Broadway Blues

https://digitalcommons.library.umaine.edu/mmb-vp/3849/thumbnail.jp

Blues : My Naughty Sweetie Gives To Me

https://digitalcommons.library.umaine.edu/mmb-vp/1113/thumbnail.jp

Where are macrophage-tropic viruses?

Eradication strategies must consider all cellular sources of virus. During the course of infection, HIV-1 can evolve to acquire new cell tropism. We have examined virus in blood and cerebral spinal fluid to identify virus capable of infecting macrophages

HIV-1 Pathogenesis: The Virus

Transmission of HIV-1 results in the establishment of a new infection, typically starting from a single virus particle. That virion replicates to generate viremia and persistent infection in all of the lymphoid tissue in the body. HIV-1 preferentially infects T cells with high levels of CD4 and those subsets of T cells that express CCR5, particularly memory T cells. Most of the replicating virus is in the lymphoid tissue, yet most of samples studied are from blood. For the most part the tissue and blood viruses represent a well-mixed population. With the onset of immunodeficiency, the virus evolves to infect new cell types. The tropism switch involves switching from using CCR5 to CXCR4 and corresponds to an expansion of infected cells to include naïve CD4+ T cells. Similarly, the virus evolves the ability to enter cells with low levels of CD4 on the surface and this potentiates the ability to infect macrophages, although the scope of sites where infection of macrophages occurs and the link to pathogenesis is only partly known and is clear only for infection of the central nervous system. A model linking viral evolution to these two pathways has been proposed. Finally, other disease states related to immunodeficiency may be the result of viral infection of additional tissues, although the evidence for a direct role for the virus is less strong. Advancing immunodeficiency creates an environment in which viral evolution results in viral variants that can target new cell types to generate yet another class of opportunistic infections (i.e., HIV-1 with altered tropism)

Integrating the HIV-1 assembly/maturation pathway

In PNAS, Jurado et al. (1) describe an unexpected mechanism of action of a new class of HIV type 1 (HIV-1) integrase (IN) inhibitors. Several years ago it was discovered that the HIV-1 IN was targeted to sites in chromatin by the host protein lens epithelium-derived growth factor (LEDGF)/p75 (2). The site of interaction between IN and LEDGF/p75 was defined, and inhibitors to block that interaction were sought and identified. In PNAS, Jurado et al. (1) show that although these inhibitors (termed Allosteric IN inhibitors, or ALLINIs) have some potency to block steps involved in integration, their most dramatic effect is to cause the virus particle to assemble into a noninfectious structure

The HIV/SIV Envelope Protein: From Structure To Function To Host Evasion

It is a pleasure to write an introduction for this collection of five short reviews of primate lentivirus Env proteins. These are very timely reviews, each designed to cover a different aspect of the biology of these proteins. This is a remarkable time to organize what we know about this family of proteins. There has been a long-standing interest in these proteins for their role in viral entry. The Env protein is the only viral protein on the surface of the virion making it the sole protein involved in entry. The synthesis of the Env protein is somewhat unremarkable, being a typical type 1 transmembrane protein synthesized as a large precursor on the rough ER. There is the co-translational addition of carbohydrate within the ER and trimerization of the Env protein precursor. Then in the golgi, a host protease cleaves the larger precursor into an extracellular surface protein (SU subunit) and a transmembrane protein (TM subunit), creating a new N terminus of the TM protein that functions as the fusion peptide in the fusion event. Despite this cleavage event, the SU and TM proteins remain together, with three of each subunit comprising an Env trimer