Longitudinal studies of viral sequence, viral phenotype, and immunologic parameters of human immunodeficiency virus type 1 infection in perinatally infected twins with discordant disease courses

Abstract

Perinatal human immunodeficiency virus type 1 (HIV-1) infections cause a broad spectrum of clinical disease and are variable in both the age of the patient at onset of serious disease and the progression of the clinical course. Heterozygotic perinatally infected twins with a marked difference in their clinical courses were monitored during the first 2 years of life. Twin B, the second-born twin, developed AIDS by 6 months of age and died at 22 months of age, while twin A remained minimally symptomatic through the first 2 years. Sequential blood specimens were obtained from the twins in order to characterize the immunologic properties of the children and the phenotypes and genotypes of the HIV-1 isolates at various times. Twin A developed neutralizing antibodies and a high-level antibody-mediated cellular cytotoxicity (ADCC) response, while twin B had no neutralizing antibody and a much lower ADCC response. The virus isolates obtained from the two children at various time points proliferated equally well in peripheral blood mononuclear cells, were nonsyncytium inducing, and could not infect established T-cell lines. They differed in their ability to infect primary macrophages. In parallel to the biological studies, the HIV-1 tat and part of the env gene sequences of the longitudinal isolates at four time points were determined. Sequences of virus from both twins at different time points were highly conserved; the viruses evolved at a similar rate until the last analyzed time point, at which there was a dramatic increase in sequence diversity for the sicker child, especially in the tat gene. Our results show that the viruses isolated at different times do not have significant changes in growth properties. The absence or low levels of neutralizing antibodies may correlate with disease progression in the twins.

Cellular tropisms and co‐receptor usage of HIV‐1 isolates from vertically infected children with neurological abnormalities and rapid disease progression

“…These data are consistent with two prior longitudinal studies in vertically HIV-1-infected children [Hutto et al, 1996;Fitzgibbon et al, 1998], and they suggest that progression of HIV-1 illness in very young children frequently does not associate with SI virus phenotype. In a study of 48 children, Fitzgibbon et al [1998] observed that rapid progressors in that cohort were no more likely to produce SI than NSI viruses, and some rapid progressors died without manifesting SI strains.…”

“…In a study of 48 children, Fitzgibbon et al [1998] observed that rapid progressors in that cohort were no more likely to produce SI than NSI viruses, and some rapid progressors died without manifesting SI strains. Hutto et al [1996] studied viral genetic diversity and cellular tropisms in perinatally infected twins with discordant disease courses, and found that the rapid progressor twin did not produce SI or T-tropic isolates from peripheral blood.…”

“…The immune response and possibly other selective pressures may act on the viral envelope glycoprotein gene region during infection to drive the evolution of the virus population toward expanding cell tropisms and increased cytopathicity. Several studies, including our own, have shown that viral sequences in the envelope glycoprotein are more homogeneous early in infection, and sequence diversity increases with disease progression and a fall in CD4 T-cell count [Hutto et al, 1996;Nowak and Bangham, 1996;Salvatori et al, 1997;Markham et al, 1998]. Most viruses isolated from adults and children close to the time of transmission are macrophage tropic and non-syncytium-inducing (NSI) [Roos et al, 1992;Spencer et al, 1994;Balotta et al, 1997], and they use predominantly chemokine receptor CCR5 as co-receptor [Zhang et al, 1998].…”

Fifteen years of Env C2V3C3 evolution in six individuals infected clonally with human immunodeficiency virus type 1

“…A multitude of longitudinal investigations on the genetic evolution of HIV-1 has been published. Particular attention has been devoted to the region of the viral env gene which encodes the viral surface glycoprotein gp120 Simmonds et al, 1990;Holmes et al, 1992;Arnold et al, 1995;Hutto et al, 1996;Yamaguchi and Gojobori, 1997;Zhang et al, 1997;Templeton et al, 2004;Lemey et al, 2005]. Previous studies on env evolution showed a relationship between the degree of HIV-1 genetic diversity and disease progression.…”

Human immunodeficiency virus type 1 mother-to-child transmission and prevention: successes and controversies

“…Evidence for the relevance of nAbs in MTCT comes from a study in monkeys, which demonstrated that injection of a cocktail of HIV‐neutralizing human monoclonal antibodies (2F5, 4E10, IgGb12 and 2G12) can prevent transmission of a lentivirus challenge to infant macaques [116]. Some studies, by us and others, showed that autologous nAbs are important for the prevention of MTCT of HIV‐1 [117–121]; however, other studies have not demonstrated any relevance of these antibodies [122–124]. Recent studies demonstrated an association between high levels of nAbs against the circulating viral strain CRF‐1_AE and low intrapartum transmission of HIV‐1 [125, 126], suggesting that nAbs play a role in the prevention of late perinatal transmission and that passive immunoprophylaxis may aid in prevention.…”