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Current
HIV Research
ISSN: 1570-162X
Current HIV Research
Volume 6, Number 1, January 2008
Contents
Human Immunodeficiency Virus Interactions with CD8+
T Lymphocytes Pp. 1-9
Nitin K. Saksena, Jing Qin Wu, Simon J. Potter, John Wilkinson
and Bin Wang
[Abstract]
HIV Genes Diversify in B Cells Pp. 10-18
Samuel J. Balin, Ted M. Ross, Jeffrey L. Platt and Marilia
Cascalho
[Abstract]
Plasmacytoid Dendritic Cells Count in Antiretroviral
Treated Patients is Predictive of HIV Load Control Independent
of CD4+ T-Cell Count Pp. 19-27
Miriam Lichtner, Raffaella Rossi, Maria C. Rizza, Fabio
Mengoni Ilaria Sauzullo, Anna P. Massetti, Giuseppe Luzi,
Anne Hosmalin Claudio M. Mastroianni and Vincenzo Vullo
[Abstract]
HIV-1 Neutralizing Activity is Correlated with
Increase Levels of Chemokines in Saliva of HIV- 1-Exposed
Uninfected Individuals Pp. 28-33
Taha Hirbod, Camilla Reichard, Klara Hasselrot, Johan
Söderlund, Joshua Kimani, Job J. Bwayo, Francis Plummer,Rupert
Kaul and Kristina Broliden
[Abstract]
Human Immunodeficiency Virus-Induced Apoptosis
of Human Breast Cancer Cells Via CXCR4 is Mediated
by the Viral Envelope Protein But Does Not Require CD4 Pp.
34-42
Masafumi Endo, Asako Inatsu, Koji Hashimoto, Nobutoki
Takamune, Shozo Shoji and Shogo Misumi
[Abstract]
Plasma HIV Load and Proviral DNA Decreases After
Two Standard Antiretroviral Regimens in HIV-Positive Patients
Naïve to Antiretrovirals Pp. 43-48
Carlo Torti, Maria Eugenia Quiros-Roldan, Giuliana Cologni,
Michele Nichelatti, Francesca Ceresoli, Marcello Pinti, Milena
Nasi, Andrea Cossarizza, Giuseppe Lapadula, Silvia Costarelli,
Nino Manca, Franco Gargiulo, Michele Magoni and Giampiero
Carosi
[Abstract]
PD-1 Predicts CD4 Loss Rate in Chronic HIV-1
Infectio Better Than HIV RNA and CD38 But Not in Cryopreserved
Samples Pp. 49-58
Malin Holm, Frank Olav Pettersen and Dag Kvale
[Abstract]
Coronary Artery Bypass Graft in HIV-Infected
Patients: A Multicenter Case Control Study Pp. 59-64
F. Boccara, A. Cohen, E. Di Angelantonio, C. Meuleman,
S. Ederhy, G. Dufaitre, G. Odi, E. Teiger, G. Barbarini, G.
Barbaro, and on Behalf the French Italian Study on
Coronary Artery Disease in AIDS Patients (FRISCA-2)
[Abstract]
Risk Factors for Nevirapine-Associated Rash Among
HIV Infected Patients with Low CD4 Cell Counts in Resource
Limited Settings Pp. 65-69
Sasisopin Kiertiburanakul, Somnuek Sungkanuparph, Angkana
Charoenyingwattana, Surakameth Mahasirimongkol, Thanyachai
Sura and Wasun Chantratita
[Abstract]
Haemostatic Activation in HIV Infected Patients
Treated with Different Antiretroviral Regimens Pp.
70-76
Angelo Pan, Sophie Testa, Eugenia Quiros Roldan, Carmine
Tinelli, Umberto Bodini, Barbara Cadeo, Giuseppe Carnevale,
Ida Martinelli, Renato Maserati, Pietro Morstabilini, Elena
Seminari, Liana Signorini and Giampiero Carosi
[Abstract]
Increase in the Non-HIV-Related Deaths Among
Aids Cases in the HAART Era Pp. 77-81
Ana M. Novoa. Patricia G. de Olalla, Roser Clos, Angels
Orcau Maica Rodríguez-Sanz and Joan A. Caylà
[Abstract]
Dietary Intake and Physical Activity in a Canadian
Population Sample of Male Patients with HIV Infection and
Metabolic Abnormalities Pp. 82-90
Bianca Maria Arendt, Elaheh Aghdassi, Saira Saddia Mohammed,
Lillia Yan Fung, Pegah Jalali, Irving Elliot Salit and Johane
Pierette Allard
[Abstract]
Abstracts
[Back to top]
Human Immunodeficiency Virus Interactions
with CD8+ T Lymphocytes
Nitin K. Saksena, Jing Qin Wu, Simon J. Potter, John Wilkinso
and Bin Wang
Human immunodeficiency virus (HIV)-specific CD8+ T cells
can mediate anti-HIV activity by both cytolytic (cytotoxic
T lymphocyte or CTL) and non-cytolytic mechanisms (antiviral)
and play a crucial role in HIV pathogenesis. Both mechanisms
actively contribute to the control of HIV in vivo.
The non-cytolytic CD8+T cells from individuals infected with
HIV suppress virus replication in CD4+ T cells in vitro
by a non-cytolytic mechanism that involves interplay of several
chemokines and an unidentified secreted soluble CD8 (+)-cell
antiviral factor (CAF). There is immense value of these two
distinct CD8 activities in anti-HIV responses and their necessity
to be maintained during highly active antiretroviral therapy
(HAART). The aim of this review is to provide an overview
of some of the novel aspects of CD8+ T cell interactions with
HIV, their role in HIV pathogenesis, HAART therapy, HIV disease
progression, gene expression and interactions with other cell
types during HIV infection.
[Back to top]
HIV Genes Diversify in B Cells
Samuel J. Balin, Ted M. Ross, Jeffrey L. Platt and Marilia
Cascalho
Mutation of the human immunodeficiency virus by host
cells inhibits viral dissemination by creating non-functional
variants. However, viral mutation does not always eliminate
the ability of the virus to disseminate and, in fact, is thought
to promote persistence by generating functional mutants that
evade immunity or drugs. How and where HIV mutates is not
known. Accordingly, where and to what extent variants emerge
may be determined by the cell type with optimal mutation apparatus
as well as by the properties of the viral genomic sequence
itself. Here we considered that HIV, which can infect B cells,
may co-opt the Ig somatic hypermutation machinery to generate
functional variants and asked whether the HIV envelope coding
sequence can diversify in B cells. We show that an HIV envelope
coding sequence transfected into B cells mutates in a manner
consistent with somatic hypermutation, causing the production
of viral protein variants. This result demonstrates that B
cells can express and diversify HIV proteins. Thus, B cells
may contribute to viral evasion and to the development of
multi-drug resistance.
[Back to top]
Plasmacytoid Dendritic Cells Count in Antiretroviral-Treated
Patients is Predictive of HIV Load Control Independent of
CD4+ T-Cell Count
Miriam Lichtner, Raffaella Rossi, Maria C. Rizza, Fabio
Mengoni, Ilaria Sauzullo, Anna P. Massetti, Giuseppe Luzi,
Anne Hosmalin, Claudio M. Mastroianni and Vincenzo Vullo
The depletion in circulating dendritic cells (DCs) and
inverse correlation with viral load have been described in
human immunodeficiency virus (HIV)-infected patients. The
aim of this study was to investigate whether the DC blood
count in antiretroviral-treated patients might be predictive
of viral load control independent of CD4+ T cell count. Plasmacytoid
DCs (pDCs) and myeloid DCs (mDCs) were enumerated using a
newly developed flow cytometric assay based on TruCOUNT. A
significant reduction of circulating pDCs and mDCs was detected
both in untreated and -treated subjects. The probability of
experiencing viral load increase according to pDC, and CD4
count at baseline was evaluated in 39 treated patients. Individuals
with lower baseline pDCs were more likely to have an increase
of HIV-RNA during the 30 month follow-up in comparison with
patients with high pDCs (p <0.001). In particular, the
pDC measurement may be useful in the context of a high CD4
count, to distinguish the patients who have virological failure
despite high CD4 counts. These findings suggest that in treated
patients the enumeration of circulating DCs, especially pDC
count, can augment the predictive value of CD4 measurement
in predicting virologic failure.
[Back to top]
HIV-1 Neutralizing Activity is Correlated with Increased Levels
of Chemokines in Saliva of HIV- 1-Exposed Uninfected Individuals
Taha Hirbod, Camilla Reichard, Klara Hasselrot, Johan
Söderlund, Joshua Kimani, Job J. Bwayo, Francis Plummer,
Rupert Kaul and Kristina Broliden
Aim: Mucosal HIV-1 exposure stimulates a variety of mucosal
immune responses, including IgA1-mediated virus neutralization,
even in the absence of an established infection. We hypothesized
that other immune molecules might also contribute to the HIV-1
neutralizing activity observed in the mucosal secretions of
HIV-1 exposed uninfected individuals. Methods: Saliva
samples were collected from HIV-1 seronegative high-risk female
sex workers (FSW) from Nairobi. Samples were also collected
from HIV-1 IgG positive FSW and HIV-1 IgG negative low-risk
women from the same geographical area. In all samples, IgA2,
secretory leukocyte protease inhibitor (SLPI), regulated on
activation, normal T-cell expressed and secreted (RANTES),
macrophage inflammatory protein 1 alpha and beta (MIP-1α
and -β)
and monocyte chemoattractant protein-1 (MCP-1) were quantified.
The IgA1-depleted saliva samples were subsequently tested
for neutralizing capacity in a PBMC-based neutralization assay
using a primary HIV-1 clade A isolate to determine biological
relevance of the measured molecules. Results: HIV-1
specific neutralization was present in the IgA1-depleted fraction
from saliva of both HIV-1 seropositive (9 of 10) and high-risk
individuals (36 of 45) but not in HIV-1 IgG-negative control
subjects (0 of 8). In the high-risk individuals, higher levels
of CC-chemokines were seen in those that could neutralize
HIV-1 as compared with those that could not (P<0.05). Conclusion:
The HIV-1 neutralizing activity in saliva of HIV-1-exposed
high-risk individuals is not only mediated by IgA1, but is
also present in IgA1-depleted fractions and is associated
with increased levels of CC-chemokines. Such innate immune
factors may be important in limiting HIV-1 mucosal transmission.
[Back to top]
Human Immunodeficiency Virus-Induced Apoptosis of Human Breast
Cancer Cells Via CXCR4 is Mediated by the Viral Envelope
Protein But Does Not Require CD4
Masafumi Endo, Asako Inatsu, Koji Hashimoto, Nobutok Takamune,
Shozo Shoji and Shogo Misumi
HIV-1 infection results in an increased risk of malignancy
as well as immune suppression. However, analyses of cancer
incidence in chronically immunosuppressed transplant recipients
and HIV-infected person have demonstrated an unexpected low
incidence of certain types of cancer, such as breast cancers,
and the mechanism behind this remains unclarified. In this
study, we show that most breast cancer cell lines express
CXCR4 but are not susceptible to HIV-1 infection. The apoptosis
of breast cancer cells is induced by HIV-1 in a viral-dose-
and time-dependent manner without productive infection. The
apoptosis is induced by R5X4 and X4 HIV-1 but not by R5 HIV-1,
and is inhibited by an anti-CXCR4 antibody, an anti-gp120
antibody, AMD3100, or pertussis toxin. The apoptosis is mediated
via CXCR4 in breast cancer cells that exhibit conformational
heterogeneity in comparison with CXCR4 in T-cells. Furthermore,
the gp120 mutant (E370R) with a low CD4 binding ability can
specifically induce apoptosis in breast cancer cells but not
in T-cells. Taken together, these results indicate that HIV-1
and gp120 can induce breast cancer cell apoptosis through
gp120-CXCR4 interaction without a CD4-induced conformational
change of gp120, and may lead to a novel HIV-1-based therapy
for breast cancer.
[Back to top]
Plasma HIV Load and Proviral DNA Decreases After Two Standard
Antiretroviral Regimens in HIV-Positive Patients Naïve
to Antiretrovirals
Carlo Torti, Maria Eugenia Quiros-Roldan, Giuliana Cologni,
Michele Nichelatti, Francesca Ceresoli, Marcello Pinti, Milena
Nasi, Andrea Cossarizza, Giuseppe Lapadula, Silvia Costarelli,
Nino Manca, Franco Gargiulo, Michele Magoni and Giampiero
Carosi
(i) To compare early decrease of HIV plasma viral load
(pVL) after two standard combinations of highly active antiretroviral
therapy (HAART). (ii) To evaluate variations of proviral
HIV-DNA load on conditions of sustained pVL undetectability.
Two different sub-studies of a multicentre prospective randomized
controlled trial which compared two first-line HAART (i.e.,
zidovudine+ lamivudine+lopinavir/ritonavir versus
tenofovir+lamivudine+ efavirenz). Only patients enrolled at
the coordinating centre (University of Brescia) were included
in the two sub-studies. In the first sub-study, we calculated
pVL decrease with respect to baseline at any of the following
time-points: days 1, 3, 7, 14 and 28. Decreases of the pVL
were compared between the two treatment groups. In the second
sub-study, we analyzed variation of proviral HIV-DNA load
in CD4+ T-cells from baseline to week 52 only in patients
who maintained the same treatment regimen and had sustained
undetectable pVL. In either studies, linear regression analysis
was used to investigate what factors could influence variations
of pVL and of proviral HIV-DNA load. (i) 64 patients
were studied. A significant decrease of pVL was found from
day 3 on, without statistically significant differences between
the two study groups. However, after adjusting for possible
confounders, tenofovir+lamivudine+efavirenz resulted to be
associated with greater pVL decreases. (ii) 45 patients
were studied. Mean proviral HIV-DNA load decreased from 1,610
(95%CI: 879-2,341) to 896 (95% CI 499-1,293) copies/10
6 cells (P=0.05). Linear regression analysis
showed that the decrease of proviral DNA load during follow-up
was independently and inversely correlated with age. Further
studies are needed to compare pVL decay between antiretroviral
regimens and assess whether proviral HIV-DNA load is a surrogate
marker of treatment effectiveness.
[Back to top]
PD-1 Predicts CD4 Loss Rate in Chronic HIV-1 Infection Better
Than HIV RNA and CD38 But Not in Cryopreserved Samples
Malin Holm, Frank Olav Pettersen and Dag Kvale
The immunopathogenic factor programmed cell death 1 (PD-1)
was compared to CD38 and HIV RNA in predicting actual CD4+
T cell loss rate indicative for clinical progression. This
cross sectional exploratory study included 50 consecutive,
healthy HIV-infected patients off antiretroviral therapy (ART);
43 had the required observation times > 12 months. PD-1
and CD38 were determined on various T cell subsets by FACS
analyses in fresh and later in parallel cryopreserved samples.
Here more rapid progressors were relatively defined by having
CD4 loss rates < median at -45.7/
μ l/year.
PD-1 and CD38 densities in fresh blood were lower (p<0.001)
in patients on ART (n=14) and seronegative controls (n=8).
CD4 loss rates correlated significantly to current HIV RNA
(R=-0.30), CD38 (R=-0.33) and PD-1 densities (R=-0.38) on
CD8+ T cells, and best to ΔCD38,
i.e. the difference in CD38 between the PD-1+CD8+ and CD8+
subsets (R=-0.51). PD-1 was highest on the CD27+CD28-CD8+
subset with best correlation to progression (R=-0.54) in rapid
progressors. Lo-gistic regression models from HIV RNA, CD38
and PD-1 predicting rapid progression included PD-1 as best
independent variable in combination with ΔCD38
or CD38, supported by similar results from multiple regression
analyses. PD-1 did not correlate with any of the other candidate
variables. Cryopreservation reduced the CD38+ and PD-1+ fractions
but cor-responding densities became more suppressed through
a non-linear loss most pronounced in CD38hi/PD-1hi cells with
loss of predictive power. In conclusion, PD-1 was the best
independent predictor for CD4 loss rates in fresh blood compared
with CD38 and HIV RNA.
[Back to top]
Coronary Artery Bypass Graft in HIV-Infected Patients: A Multicenter
Case Control Study
F. Boccara, A. Cohen, E. Di Angelantonio, C. Meuleman,
S. Ederhy, G. Dufaitre, G. Odi, E. Teiger, G. Barbarini, G.
Barbaro, and on Behalf the French Italian Study on
Coronary Artery Disease in AIDS Patients (FRISCA-2)
Coronary artery disease (CAD) is an emerging complication
in HIV-infected patients treated with highly active antiretroviral
therapy. Immediate results and long-term outcome after coronary
artery bypass graft (CABG) have not been yet evaluated in
this population. Between January 1997 and December 2005, we
compared baseline characteristics, immediate results and clinical
outcome [Major Adverse Cardiac Events (MACE): death for cardiac
cause, myocardial infarction (MI), coronary revascularization]
at 41 months in 27 consecutive HIV-infected (HIV+) patients
and 54 HIV-uninfected (HIV-) controls matched for age and
gender (mean age of the cohort, 49 ±8
years; 96% male) who underwent CABG. Cardiovascular risk factors
were well-balanced and nearly identical in both groups. In
HIV+ group, mean preoperative CD4 was 502 ±192/mm
3 compared with 426.2 ±152.6/mm3
postoperatively (p=0.004) without clinical manifestations
at follow-up. At 30-day, the rate of post-operative death,
MI, stroke, mediastinitis, re-intervention was identical in
both groups. At follow-up [median: 41-months (range: 34-60)],
rate of occurrence of 1ST
MACE was higher in HIV+ group compared with HIV- group (11,
42% versus 13, 25%, p=0.03), mostly due to the need of repeated
revascularization using percutaneous coronary intervention
of the native coronary arteries but not of the grafts in the
HIV+ group [9 (35%) versus 6 (11%), p=0.02]. CABG is a feasible
and safe revascularization procedure in HIV+ patients with
multivessel CAD. Immediate postoperative outcome was similar
compared to controls. However, long-term follow-up was significantly
different, due to an increased rate of repeated revascularization
procedure in the native coronary arteries of HIV+ patients.
[Back to top]
Risk Factors for Nevirapine-Associated Rash Among HIV Infected
Patients with Low CD4 Cell Counts in Resource Limited Settings
Sasisopin Kiertiburanakul, Somnuek Sungkanuparph, Angkana
Charoenyingwattana, Surakameth Mahasirimongkol, Thanyachai
Sura and Wasun Chantratita
Nevirapine (NVP) is commonly used as a component of first-line
antiretroviral therapy in resource-limited countries. We aimed
to determine the risk factors for NVP-associated rash among
HIV-infected patients who were initiated NVP at low CD4 cell
counts in a resource-limited setting. A case-control study
was conducted in HIV-infected patients who developed rash
after taking NVP (case) and those who did not have rash (control).
A total of 357 patients with a mean (SD) age of 36.4 (7.5)
years and 52.1% male were included in the study. Mean body
weight (SD) was 55.5 (10.5) kg. Of all, 179 (49.0%) patients
had a history of AIDS-defining illness and 57 (16.0%) patients
had history of drug allergy. Median (IQR) CD4 cell counts
at the time of NVP initiation was 95 (31-226) cells/mm3.
There were 115 patients in case group and 242 patients in
control group. In case group, 43.0%, 54.4%, and 2.6% of patients
developed grade 2, 3, and 4 of rash, respectively. Median
time to develop rash was 12 (95%CI, 10.5-13.5) days. By logistic
regression, history of drug allergy (OR, 3.41; 95%CI, 1.79-6.52),
body weight (OR, 1.22 per each 5 kg decrement; 95%CI, 1.08-1.38),
CD4 cells counts (OR, 1.20 per each 50 cells/mm3
increment; 95%CI, 1.12-1.30), and AIDS-defining
illness (OR, 0.42; 95%CI, 0.25-0.70) were significantly associated
with rash. In resource-limited settings where patients were
initiated NVP at low CD4 cell counts, history of drug allergy,
lower body weight, and higher CD4 cell count are the risk
factors for NVP-associated rash. Initiation of NVP in patients
with these risks needs closed monitoring.
[Back to top]
Haemostatic Activation in HIV Infected Patients Treated with
Different Antiretroviral Regimens
Angelo Pan, Sophie Testa, Eugenia Quiros Roldan, Carmine
Tinelli, Umberto Bodini, Barbara Cadeo, Giuseppe Carnevale,
Ida Martinelli, Renato Maserati, Pietro Morstabilini, Elena
Seminari, Liana Signorini and Giampiero Carosi
HIV infected patients treated with highly active antiretroviral
therapy (HAART) may be at increased risk of cardiovascular
events, particularly if based upon the use of protease inhibitors
(PI). We investigated the haemostatic markers of cardiovascular
risk in 115 HIV infected subjects, divided into four groups:
1) patients naïve to antiretroviral therapy (Naïve;
n=34 patients), or subjects that had been on a stable
combination therapy for =12 months with either: 2) double
reverse transcriptase nucleoside analogue inhibitors therapy
(2NRTI; n=26), 3) 2NRTI backbone plus a non-nucleoside
analogue reverse transcriptase inhibitor (NNRTI; n=27),
and 4) on a PI based regimen (PI; n=28). Forty-four
healthy subjects were included as controls. Naïve as
well as 2NRTI and NNRTI differed from controls for higher
F1+2 (P<.0001) and FVII (P<.007) levels.
When comparing PI patients with controls we observed significantly
higher levels of Fbg (P=.035), FVII (P<.0001),
TM (P<.0089), vWF (P=.009), and F1+2 (P<.0001).
The only difference observed among the 4 groups of HIV infected
patients was a significantly lower level of F1+2 in PI as
compared with NNRTI patients (P=.05) At least one
ab-normal result was observed in = 90.6% of HIV infects groups,
vs 43.2% of controls (P<.0001 in all cases). In
conclusion, a) HIV infection per se may alter the
haemostatic markers of cardiovascular risk, b) minor differences
were observed among the different classes of HIV infected
patients, namely between NNRTI and PI treated patients.
[Back to top]
Increase in the Non-HIV-Related Deaths Among Aids Cases in
the HAART Era
Ana M. Novoa. Patricia G. de Olalla, Roser Clos, Angels
Orcau, Maica Rodríguez-Sanz and Joan A. Caylà
Objective: To analyze the factors associated with survival
and to describe the specific causes of death in a large cohort
of individuals with Acquired Immune Deficiency Syndrome (AIDS)
in the Highly Active Antiretroviral Therapy (HAART) era. Methods:
Subjects over 13 years old recorded in the AIDS registry of
Barcelona and diagnosed between 1997-2005 were included. Survival
analysis was performed. Causes of death were classified as
being HIV-related or non-HIV-related. Results: A
total of 1,759 cases were analyzed, 640 (36.3%) of them died
during the follow-up. The cumulative probability of survival
at five years was of 64% (95% C.I. 62%-67%). The cause of
death was non-HIV-related in 28.9% of the cases, among which
the most frequent were cancers (20.8%) and liver diseases
(18.8%). Conclusion: An increase in the proportion
of non-HIV-related deaths has been observed compared to that
in the pre-HAART era. The case management of HIV-infected
people must be re-directed to influence the risk factors associated
with these increasing causes of death.
[Back to top]
Dietary Intake and Physical Activity in a Canadian Population
Sample of Male Patients with HIV Infection and Metabolic Abnormalities
Bianca Maria Arendt, Elaheh Aghdassi, Saira Saddia Mohammed,
Lillia Yan Fung, Pegah Jalali, Irving Elliot Salit and Johane
Pierette Allard
Objective was to assess dietary intake and physical activity
in a Canadian population sample of male patients with HIV
and metabolic abnormalities and to compare the data to Canadian
recommendations. Sixty-five HIV-infected men with at least
one feature associated with the metabolic syndrome (insulin
resistance, dyslipidemia, central obesity, or lipodystrophy)
were enrolled. Results from 7-day food records and activity
logs were compared to the Dietary Reference Intakes and recommendations
of Canada’s Physical Activity Guide, respectively. Anthropometric
data were also measured. Fifty-two percent of the subjects
were overweight, another 15% were obese. However, energy intake
(mean ±
SEM) (2153 ±
99 kcal/d) was lower than the estimated requirement (2854
± 62
kcal/d; p<0.0001), and 84.5% of the patients reached the
recommended minimum of 60 min of mild or 30 min of moderate
daily exercise. Intake was adequate for protein, but high
for fat and cholesterol in 40% of patients. No patient reached
the recommendation for fiber. Intake from diet alone was suboptimal
for most micronutrients. Prevalence was highest for low vitamin
E (91% of patients) and magnesium (68%) intake, and high sodium
intake (72%). In summary, a large proportion of HIV patients
with metabolic abnormalities were overweight or obese. However,
this was not associated with high energy intake, or reduced
physical activity. High fat, low fiber and inadequate micronutrient
intakes were prevalent.
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