ABSTRACT
HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.
Subject(s)
HIV-1/pathogenicity , Host Specificity , Human Immunodeficiency Virus Proteins/immunology , Lentiviruses, Primate/growth & development , Simian Immunodeficiency Virus/pathogenicity , Viral Regulatory and Accessory Proteins/immunology , nef Gene Products, Human Immunodeficiency Virus/immunology , Amino Acid Sequence , Animals , Bone Marrow Stromal Antigen 2/genetics , Bone Marrow Stromal Antigen 2/immunology , CD3 Complex/genetics , CD3 Complex/immunology , Chlorocebus aethiops , Female , Gene Expression Regulation , HIV-1/growth & development , Human Immunodeficiency Virus Proteins/genetics , Humans , Lentiviruses, Primate/pathogenicity , Lymphocyte Activation , NF-kappa B/genetics , NF-kappa B/immunology , Sequence Alignment , Signal Transduction , Simian Immunodeficiency Virus/growth & development , Transcription, Genetic , Viral Load , Viral Regulatory and Accessory Proteins/genetics , Virulence , Virus Replication , nef Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
Subject(s)
Amyloid/antagonists & inhibitors , Anti-HIV Agents/pharmacology , Antimetabolites/pharmacology , Bridged-Ring Compounds/pharmacology , Organophosphates/pharmacology , Semen/drug effects , Disease Transmission, Infectious/prevention & control , HIV Infections/prevention & control , HIV Infections/transmission , Humans , Male , Semen/chemistry , Semen/virologyABSTRACT
Contact between the human immunodeficiency virus (HIV-1) and its target cell is initiated by the interaction of viral gp120 with cellular CD4. An assembled peptide (CD4bs-M) that presents the CD4 binding site of gp120 was previously shown to inhibit the gp120-CD4 interaction. Here, we demonstrate that CD4bs-M selectively enhances infection of cells with HIV-1, whereas infection with herpes simplex virus remains largely unaffected. The effects of CD4bs-M variants containing D-amino acids, or prolines at selected positions, point to the importance of side chain orientation and spatial orientation of this fragment. Furthermore, CD4bs-M was shown to assemble into amyloid-like fibrils that capture HIV-1 particles, which likely contributes to the infection-enhancing effect. Beyond infection enhancement, CD4bs-M enabled HIV-1 infection of CD4-negative cells, suggesting that binding of the peptide to gp120 facilitates interaction of gp120 with coreceptors, which might in turn enhance HIV-1 entry.
