Early Changes in Quasispecies Repertoire in HIV-Infected Infants: Correlation with Disease Progression

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccineassociated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.Infection with human immunodeficiency virus type 1 (HIV-1) leads to eventual immune attrition and the onset of AIDS. The rate of disease progression, however, is variable and appears to be determined, in part, by the nature of the immune response against the virus. Long-term slow progressors, for example, typically exhibit a broad range of antiviral responses, particularly cell-mediated immunity. Such individuals also harbor diverse viral quasispecies, and several recent reports have shown that this high degree of viral diversity is a direct consequence of immune selection pressure. (4,8,14) Attempts to boost specific immunity with HIV-1 recombinant glycoprotein (RGP) vaccines have resulted in some HIVinfected individuals developing augmented humoral and cellular immune responses. (7,12,15) Whether these vaccineassociated immune responses correlate with any change in the repertoire of viral quasispecies remains unknown.The objectives of the current study were to characterize quasispecies diversity at baseline in a group of 12 asymptomatic HIV-1-infected children who received either placebo or RGP vaccines and to determine whether these vaccines generate an added immunologic selection pressure capable of driving viral evolution. The vaccines studied were all recombinant envelope proteins; therefore, we assayed changes in the diversity of the viral envelope-the region of the genome most likely to be affected by a vaccine-associated immune response.The number of patients evaluated was small; however, our results suggest that RGP vaccination in these children did not drive viral evolution. Indeed, there seemed to be an inverse relationship between vaccine-associated immune response and the degree of viral diversity. Although the study sample was small, these findings are provocative, and we believe that the results merit further study in a larger cohort of patients. These data highlight the importance of measuring viral diversity to evaluate the efficacy of therapeutic HIV vaccination. MATERIALS AND METHODSPatients and vaccines. A...

show abstract

“…(3,6). In keeping with these findings, we noted that most of our asymptomatic HIV-infected children had multiple env variants at baseline.…”

Section: Discussionsupporting

confidence: 80%

“…There are several methods of measuring the degree of diversity in HTAs (3,6). The most widely accepted uses an entropy analysis to determine how ordered the distribution of signal intensity is along the length of a gel lane (3).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Glycoprotein Vaccines for Human Immunodeficiency Virus-Infected Children and Their Effects on Viral Quasispecies

Essajee

Yogev

Pollack

et al. 2002

Clin Vaccine Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many studies have evaluated HIV-1 subtype B diversity at single and sequential time points and its correlation with disease progression (1,7,11,15,18,20,22,24,25,40,41,43,47). These studies included individuals treated with antiretroviral drugs and sampled both during the disease-free interval and once clinical AIDS was established.…”

Section: Discussionmentioning

confidence: 99%

“…This is particularly the case with HIV-2 and HIV-1 infections, for HIV-2 viral loads appear to be significantly lower than HIV-1 viral loads over the course of infection. (33) Most previous studies have sought to examine the correlation between disease progression and intrapatient diversity in subtype B-infected individuals, both adults (1,18,20,22,24,25,40,41,47) and children (7,11,15,43), excepting a study examining viral evolution in nonrecombinant subtype A-infected women from Kenya (34) and a study by Sutthent et al which revealed a correlation between poorer clinical status and increased diversity in subtype E-infected mothers and their infants (44). The majority of studies have evaluated regions of the env gene, a rapidly evolving and functionally important region.…”

mentioning

confidence: 99%

Intrapatient Diversity and Its Correlation with Viral Setpoint in Human Immunodeficiency Virus Type 1 CRF02_A/G-IbNG Infection

Mani

Gilbert

Sankalé

et al. 2002

J Virol

View full text Add to dashboard Cite

The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the diseasefree interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-naïve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1|؊|log 10 copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P ‫؍‬ 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P ‫؍‬ 0.01). Greater nucleotide (P ‫؍‬ 0.015) and amino acid (P ‫؍‬ 0.048) divergences and a greater nucleotide divergence rate (P ‫؍‬ 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.

show abstract

“…By contrast, other researchers have reported high rates of sequence divergence to be associated with slow disease progression [18][19][20]. Similarly, multiple studies have reported that HIV-1 populations diversify faster in people progressing slowly to AIDS than in those who develop disease more rapidly [16,19,[21][22][23][24] and that genetic changes appear to be associated with stronger positive selection in people who progress slowly to AIDS [18][19][20][21][25][26][27]. However, it has also been reported that rates of viral diversification are higher in HIV-1 progressors than in nonprogressors [17].…”

mentioning

confidence: 99%

Long‐Term Intrapatient Viral Evolution during HIV‐2 Infection

et al. 2007

View full text Add to dashboard Cite

Background. Disease progression and transmission of human immunodeficiency virus (HIV) type 2 are attenuated, compared with HIV-1, which is consistent with the lower plasma viral loads observed in HIV-2 infection. Although numerous studies have characterized the intrapatient evolution of viral sequences during HIV-1 infection, prospective studies examining intrapatient evolution during HIV-2 infection have been limited.Methods. We examined viral sequence evolution in the C2V3C3 region of the viral env gene in 8 HIV-2-infected individuals from Dakar, Senegal, over the course of approximately 10 years. To compare results with HIV-1 infection, we reanalyzed data from our previous study that prospectively examined intrapatient viral evolution in HIV-1-infected individuals from the same population.Results. HIV-2 sequences from early and late time points were phylogenetically intermixed for all subjects. No distinct trends were observed in terms of increases or decreases in fragment size or the number of N-linked glycosylation sites, and ratios of synonymous substitutions per synonymous site to nonsynonymous substitutions per nonsynonymous site suggested selection to be neutral or negative. In homologous env C2V3 sequences, rates of viral divergence and diversification were slower in individuals infected with HIV-2 than in those infected with HIV-1.Conclusions. Viral evolution occurs slowly in HIV-2 infection, which is consistent with the slow disease progression of HIV-2 and supports the notion that viral evolution may be a relevant correlate for disease progression.

show abstract

Early Changes in Quasispecies Repertoire in HIV-Infected Infants: Correlation with Disease Progression

Cited by 16 publications

References 39 publications

Recombinant Glycoprotein Vaccines for Human Immunodeficiency Virus-Infected Children and Their Effects on Viral Quasispecies

Recombinant Glycoprotein Vaccines for Human Immunodeficiency Virus-Infected Children and Their Effects on Viral Quasispecies

Intrapatient Diversity and Its Correlation with Viral Setpoint in Human Immunodeficiency Virus Type 1 CRF02_A/G-IbNG Infection

Long‐Term Intrapatient Viral Evolution during HIV‐2 Infection

Contact Info

Product

Resources

About