HIV subtypes and recombination strains-strategies for induction of immune responses in man
Britta WahrénKarl LjungbergErik RollmanMichael LeviBartek ZuberAnne Kjerrström ZuberJorma HinkulaA.‐C. LEANDERSSONSandra A. CalarotaBo HejdemanGöran BrattEric Sandström
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V3 loop
HIV Antigens
Human immunodeficiency virus type 1 (HIV-1) strains display a high degree of heterogeneity in their biological properties that correlate with in vivo pathogenesis of the virus. We previously demonstrated that overlapping regions encompassing the third hypervariable domain (V3), within the envelope glycoprotein gp120 determine the tropisms of HIV-1 for T-cell lines and primary macrophages. Studies with mutant viruses carrying one or more amino acid substitutions in the V3 loop have now identified this hypervariable domain as a major determinant for these cellular host range properties. Three to five amino acid changes in this domain, but rarely a single amino acid substitution, can confer macrophage tropism and alter T-cell-line tropism. These findings emphasize the effect on cell tropism of small amino acid differences in the viral envelope and suggest that the overall conformation of the V3 loop plays the major role in determining the ability of HIV-1 to infect T-cell lines and primary macrophages.
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Tissue tropism
Hypervariable region
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V3 loop
Tissue tropism
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Cells of the monocyte-macrophage lineage are targets for human immunodeficiency virus-1 (HIV-1) infection in vivo. However, many laboratory strains of HIV-1 that efficiently infect transformed T cell lines replicate poorly in macrophages. A 20-amino acid sequence from the macrophage-tropic BaL isolate of HIV-1 was sufficient to confer macrophage tropism on HTLV-IIIB, a T cell line-tropic isolate. This small sequence element is in the V3 loop, the envelope domain that is the principal neutralizing determinant of HIV-1. Thus, the V3 loop not only serves as a target of the host immune response but is also pivotal in determining HIV-1 tissue tropism.
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V3 loop
Infectivity
Tissue tropism
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The third variable (V3) region within the gp120 envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) has been reported to be an important determinant of viral tropism. In this study a series of isogenic recombinant HIV-1 viruses, containing V3 regions from fresh isolates, were examined to ascertain if a relationship exists between viral tropism and specific properties of the virion-associated envelope. All of the viruses were able to infect CD4+ primary lymphocytes, although with different infection kinetics. Several recombinants, however, were unable to infect a continuous CD4+ T-cell line permissive for the parental virus and exhibited a marked decrease in the kinetics of virion-associated gp120 binding to a soluble form of CD4. A known macrophage-tropic HIV-1 isolate, also unable to infect the T-cell line, bound CD4 with similarly slow reaction kinetics. Although the inability to infect T-cell lines is a commonly observed property of macrophage-tropic isolates of HIV-1, the loss of T-cell line tropism by the V3 recombinants was not accompanied by a substantial infectivity for monocyte-derived macrophages, as monitored by reverse transcriptase production. Additional analyses of the recombinant virion gp120s indicated that most of the V3 substitutions increased the inherent stability of the virion gp120-gp41 envelope complex. These results indicate that V3-induced alterations in viral tropism are associated with changes in physical and functional properties of the virion envelope.
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Viral Interference
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The V3 loop of human immunodeficiency virus type 1 is both a determinant of viral cell tropism and a target for neutralizing antibodies. This relationship was investigated. Selection of a dual-tropic (T cells and macrophages) virus to replicate in CD4+ brain cells results in loss of macrophage tropism and of neutralization by an anti-V3 loop monoclonal antibody. Moreover, selection of the brain-selected variant to escape from V3 loop-specific neutralizing monoclonal antibodies results in the reduction or loss of brain cell tropism and the reacquisition of macrophage tropism. These data may indicate that the antigenic diversification of human immunodeficiency virus type 1 apparent after seroconversion can be selected either by immune responses or by colonization of new cell types.
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Tissue tropism
HIV Antigens
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We and others have identified the major determinant of cell tropism in human immunodeficiency virus type 1 (HIV-1) as the V3 loop of glycoprotein gp120. We have conducted a detailed study of two molecularly cloned isolates of HIV-1, HIVJR-CSF and HIVNL4-3, that differ in their tropism for immortalized CD4+ cell lines, by constructing a series of site-directed mutations within the V3 loop of HIVJR-CSF based on the sequence of HIVNL4-3. The phenotypes of these mutants fall into two classes, those which are viable and those which are not. A spontaneous mutant with significantly altered growth properties was also recovered and found to have an additional single amino acid change in the V3 loop sequence. The carboxy-terminal beta-strand part of the V3 loop is the major determinant of cell tropism. However, the results presented here indicate that the functional role of the V3 loop sequences can only be interpreted properly in the context of the original gp120 backbone from which they were derived. These findings show that over-simplistic interpretation of sequence data derived from unknown mixtures of HIV variants in infected persons may be highly misleading.
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Laboratory isolates of human immunodeficiency virus type-1 (HIV-1) such as HTLV-IIIB are generally T cell line-tropic and highly sensitive to neutralization by soluble CD4 (sCD4), a potential antiviral agent that is undergoing clinical trial. However, many primary HIV-1 isolates are macrophage-tropic and sCD4-resistant. Envelope V3 loop sequences derived from primary HIV-1 isolates were sufficient to confer on HTLV-IIIB not only the tissue tropism but also the degree of sCD4 neutralization resistance characteristic of their HIV-1 strains of origin. Single amino acid changes in the V3 loop enhanced sCD4 resistance by up to tenfold. These observations suggest that the tissue tropism and sCD4 neutralization sensitivity of HIV-1 isolates are regulated by similar mechanisms.
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Although the B clade of human immunodeficiency virus type 1 (HIV-1) envelopes (Env) includes five highly variable regions, each of these domains contains a subset of sequences that remain conserved. The V3 loop has been much studied for its ability to elicit neutralizing antibodies, which are often restricted to a limited number of closely related strains, likely because a large number of antigenic structures are generated from the diverse amino acid sequences in this region. Despite these strain-specific determinants, subregions of V3 are highly conserved, and the effects of different portions of the V3 loop on Env tropism and immunogenicity have not been well delineated. For this report, selective deletions in V3 were introduced by shortening of the stem of the V3 loop. These mutations were explored in combination with deletions of selected V regions. Progressive shortening of the stem of V3 abolished the immunogenicity as well as the functional activity of HIV Env; however, two small deletions on both arms of the V3 stem altered the tropism of the dualtropic 89.6P viral strain so that it infected only CXCR4(+) cells. When this smaller deletion was combined with removal of the V1 and V2 loops and used as an immunogen in guinea pigs, the antisera were able to neutralize multiple independent clade B isolates with a higher potency. These findings suggest that highly conserved subregions within V3 may be relevant targets for eliciting neutralizing antibody responses, affecting HIV tropism, and increasing the immunogenicity of AIDS vaccines.
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ABSTRACT To assess the role of naturally occurring basic amino acid substitutions in the V3 loop of human immunodeficiency virus type 1 (HIV-1) subtype E on viral coreceptor usage and cell tropism, we have constructed a panel of chimeric viruses with mutant V3 loops of HIV-1 subtype E in the genetic background of HIV-1 LAI . The arginine substitutions naturally occurring at positions 8, 11, and 18 of the V3 loop in an HIV-1 subtype E X4 strain were systematically introduced into that of an R5 strain to generate a series of V3 loop mutant chimera. These chimeric viruses were employed in virus infectivity assays using HOS-CD4 cells expressing either CCR5 or CXCR4, peripheral blood mononuclear cells, T-cell lines, or macrophages. The arginine substitution at position 11 of the V3 loop uniformly caused the loss of infectivity in HOS-CD4-CCR5 cells, indicating that position 11 is critical for utilization of CCR5. CXCR4 usage was conferred by a minimum of two arginine substitutions, regardless of combination, whereas arginine substitutions at position 8 and 11 were required for T-cell line tropism. Nonetheless, macrophage tropism was not conferred by the V3 loop of subtype E R5 strain per se. We found that the specific combinations of amino acid changes in HIV-1 subtype E env V3 loop are critical for determining viral coreceptor usage and cell tropism. However, the ability to infect HOS-CD4 cells through either CXCR4 or CCR5 is not necessarily correlated with T-cell or macrophage tropism, suggesting that cellular tropism is not dictated solely by viral coreceptor utilization.
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Cell fusion
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