final program.qxd - Parallels Plesk Panel

FP 1.4
V1V2 loop length variation during HIV-1 infection
Yi Liu 2 , Wenjie Deng 2 , Geoffrey Gottlieb 1,2, , Rafael Zioni 2 , Marcel E. Curlin 1 Tuofu Zhu 2,3,
James I. Mullins 1,2,3
University of washington Departments of Medicine 1 , Microbiology 2 and Laboratory
Medicine 3 ; University of Washington School of Medicine, Seattle, Washington.
Objective We sought to determine the relationship between envelope hypervariable region
loop-length and disease progression and transmission to a new host during HIV infection.
Methods Sequences were derived from published and unpublished envelope sub-regions
from treatment-naive adult subjects harboring HIV-1 subtype B. We collected a total of
4736 gene sequences from individual subregions, derived from 455 clinical samples
(usually PBMC or plasma) from 144 subjects. Sequences were aligned using ClustalW,
translated into amino acid sequences and manually edited to identify the V1V2, C2, V3,
C3, V4, C4 and V5 regions. Subregion lengths were calculated, and potential N-linked
glycosylation sites were counted using N-glycosite. Data were analyzed treating each
sequence individually, and repeated as a weighted average of all sequences contributed
by a given individual. In cross-sectional analyses, loop length variation was examined as
a function of time since infection, CD4 count, viral load, and calendar year. In longitudinal
analyses, loop lengths were examined as a function of time between sampling. We also
examined loop-length variation during transmission to a new host. Results V1V2 displayed
the most length variation of any region examined. In cross-sectional analyses, a
significant positive correlation was observed between V1V2 length increase and time
since infection (p < 0.05), and calendar year (p < 0.05). A weak inverse relationship was
noted between V1V2 length and CD4 count. However, no relationship was seen with viral
load, or whether sequences were obtained from plasma or PBMC. In longitudinal
analyses, V1V2 loop length was generally seen to increase over time in subjects with
chronic HIV infection (not AIDS). However, in subjects with advanced disease (CD4 count
< 200), V1V2 loop length decreased over time. Transmission between hosts was usually
but not always associated with an initial decline in V1V2 loop length. V5 was the next most
variable region, but did not change in any consistent way in relationship to the parameters
examined. Changes in the number of glycosylation sites generally paralleled length
variation. Discussion Structural studies indicate that the V1V2 region shields V3 prior to
CD4 binding, and is intimately involved in conformational changes allowing coreceptor
binding site exposure, and coreceptor binding. Viruses lacking V1 and V2 replicate
efficiently in vitro, but are highly sensitive to neutralizing antibodies. Therefore, the
principal role of the V1V2 region may be to permit evasion from humoral immune
responses in the host. Our observations are consistent with the hypothesis that HIV
adapts to humoral selective pressure within the immunocompetent host by increasing the
size of V1V2, either by lengthening of the V1V2 amino-acid chain, and/or by adding
carbohydrate moieties at N-linked glycosylation sites. The significance of the apparent
increase in V1V2 length by calendar year is unclear but may be related to sampling bias.
HIV-1 V1V2 loop length may be an indirect clinical indicator of humoral immune
competence. Vaccines eliciting humoral immunity to HIV may provide greater protection
from donors with early infection and shorter V1V2 loop lengths than from donors with
chronic disease and longer V1V2 length variants.
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