Intercompartmental Recombination of HIV-1 Contributes to<i>env</i>Intrahost Diversity and Modulates Viral Tropism and Sensitivity to Entry Inhibitors

Brown, Richard J. P.; Peters, Paul J.; Caron, Catherine; Gonzalez-Perez, Maria Paz; Stones, Leanne; Ankghuambom, Chiambah; Pondei, Kemebradikumo; McClure, C. Patrick; Alemnji, George; Taylor, Stephen; Sharp, Paul M.; Clapham, Paul R.; Ball, Jonathan K.

doi:10.1128/jvi.00131-11

Cited by 50 publications

(62 citation statements)

References 93 publications

(109 reference statements)

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“…Previous studies have shown tissue-specific variations in different viral models, including arenavirus sequences isolated from the same animal (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). To avoid this bias, ML29 was isolated only from sera of vaccinated animals.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Zapata

Goicochea

Nadai

et al. 2014

J Virol

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The attenuated Lassa vaccine candidate ML29 is a laboratory-produced reassortant between Lassa and Mopeia viruses, two Old World arenaviruses that differ by 40% in nucleic acid sequence. In our previous studies, ML29 elicited sterilizing immunity against Lassa virus challenge in guinea pigs and marmosets and virus-specific cell-mediated immunity in both simian immunodeficiency virus (SIV)-infected and uninfected rhesus macaques. Here, we show that ML29 is stable after 12 passages in vitro without losing its plaque morphology or its attenuated phenotype in suckling mice. Additionally, we used deep sequencing to characterize the viral population comprising the original stock of ML29, the stock of ML29 after 12 passages in Vero cells, and the ML29 isolates obtained from vaccinated animals. Twenty-seven isolates bore approximately 77 mutations that exceeded 20% of the single-nucleotide polymorphism (SNP) changes at any single locus. Of these 77 mutations, 5 appeared to be host specific, for example, appearing in mice but not in primates. None of these mutations were reversions of ML29 to the sequences of the parental Lassa and Mopeia viruses. The host-specific mutations indicate viral adaptations to virus-host interactions, and such interactions make reasonable targets for antiviral approaches. Variants capable of chronic infection did not emerge from any of the primate infections, even in immune-deficient animals, indicating that the ML29 reassortant is reasonably stable in vivo. In conclusion, the preclinical studies of ML29 as a Lassa virus vaccine candidate have been advanced, showing high levels of protection in nonhuman primates and acceptable stability both in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Zapata

Goicochea

Nadai

et al. 2014

J Virol

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“…59,60 The concept that infected cells and viral particles in semen may arise from distinct genital organs is supported by several elements; thus, the detection of cell-free HIV RNA is not associated with that of cell-associated pro-viral DNA in semen, 14 and subcompartmentalization of HIV quasispecies between seminal cells and seminal plasma has been evidenced. 4,61 Whereas macrophage-tropic R5 strains are readily detected in cell-free seminal plasma, 62 T lymphocytes are the most commonly HIV-infected leukocytes in semen, 63 and pro-viral DNA envelope sequences in seminal cells are primarily not macrophagetropic. 64 This argues against a major contribution of the seminal vesicles to HIV-infected cells in semen because in vitro and in treated men, the bulk of infected cells in this organ is of macrophage nature.…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

Deléage

Moreau

Rioux‐Leclercq

et al. 2011

The American Journal of Pathology

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1 the precise origins of the infected leukocytes and free viral particles contaminating the seminal plasma remain unclear. Phylogenetic studies have established that HIV in semen arises from local sources within the male genital tract and/or from passive diffusion via the blood 2-4 (previous references in Le Tortorec and Dejucq-Rainsford 5 ). The existence of productive sources in the male genital tract is further substantiated through observations of several differences between blood and semen, including i) detection of persistent infectious HIV in the semen of 5% to 30% of men with undetectable blood viral load receiving fully suppressive antiretroviral therapy [5][6][7][8][9] ; ii) higher viral load in semen in a subpopulation of treatment-naïve men 10 ; iii) different rates, kinetics of emergence, and diversity of drug-resistant strains 4,11,12 ; and iv) different ratio of infected versus noninfected leukocytes. 13At present, the nature of the sources of HIV in the male genital tract remains unclear. This knowledge is crucial to the understanding of the biology of HIV sexual transmission and to the design of targeted therapies for eradicating HIV from semen.Semen is composed of secretions and cells from the testes, epididymides, prostate, seminal vesicles, and bulbo urethral glands. Vasectomy has little effect on seminal shedding of HIV-1 RNA, 14 which suggests that the testes and epididymides are not the primary sources of HIV particles in semen. The seminal vesicles, the secretions of which represent more than 60% of the seminal fluid, could be an important source of seminal HIV. We recently demonstrated that the seminal vesicles of asymptomatic macaques are productively infected by simian immunodeficiency virus (SIV) in vivo and, together with the prostate, exhibit the highest level of infection among the male genital tract organs in this animal model. 15 To date, infection of human seminal vesicles by HIV has not been reported.

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“…In this regard, HIV neurotropism is primarily determined by the viral envelope gene (13)(14)(15)(16), and compartmentalization of a genetically distinct envelope (Env) population in the CNS from that in the systemic circulation (17)(18)(19)(20), as a result of either a founder effect or independent viral adaptive evolution in the brain with long-term HIV infection, has been described (21,22). More-over, different env genotypes have been reported in different CNS regions of HIV-1-infected individuals and simian immunodeficiency virus (SIV)-infected macaques (23)(24)(25)(26), despite the use of a "clonal" inoculum in the latter (23,24), suggesting discordant regional virus evolution in this anatomical compartment, as well.…”

mentioning

confidence: 99%

Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

Zhuang

Léda

Tsai

et al. 2014

J Virol

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Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4 low cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE).Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.

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Intercompartmental Recombination of HIV-1 Contributes toenvIntrahost Diversity and Modulates Viral Tropism and Sensitivity to Entry Inhibitors

Cited by 50 publications

References 93 publications

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Genetic Variation In Vitro and In Vivo of an Attenuated Lassa Vaccine Candidate

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis

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