ORIGINAL ARTICLE
Application of Polymerase Chain Reaction to Detect HIV-1 DNA in Pools of Dried Blood Spots
Vemu Lakshmi • Talasila Sudha • Dandona Rakhi •
G. Anilkumar • Lalit Dandona
Received: 26 November 2009 / Accepted: 29 September 2010 / Published online: 28 January 2011
� Association of Microbiologists of India 2011
Abstract Nucleic acid tests that detect HIV infection at
an early phase are available and have been applied on
individual dried blood spot (DBS). The present study was
undertaken with an aim to evaluate the feasibility of per-
forming PCR for HIV-1 DNA on pools of DBS as an
alternative to individual testing. Standardization of PCR by
a modified Amplicor HIV-1 DNA assay version 1.5 (Roche
molecular diagnostics, USA), on pooled DBS was per-
formed using five confirmed HIV reactive samples with
known low viral load of HIV-1 and HIV non-reactive
samples in pools of 5, 10 and 20 DBS. After successful
standardization of pooling procedure, a total of 183 pools
(of 10 DBS each) were prepared from 1,823 DBS samples,
collected from a population-based study that tested nega-
tive for HIV antibodies and p24 antigen. All these pools
were screened for HIV-1 DNA by the Amplicor assay.
Standardization of pooling procedure indicated that pool-
ing of 10 DBS gave an optimum result. Out of 183 pools
tested, one pool of 10 samples was positive and of these ten
DBS that were tested individually to identify the positive
DBS, one sample was detected to be positive for HIV-1
DNA. Our study demonstrates that PCR for HIV-1 DNA
can be successfully performed on pools of DBS. However,
this may be needed only on specialized studies of HIV and
not for routine epidemiology studies as only a very small
fraction of cases would be missed if only antibody/antigen
testing were done.
Keywords Dried blood spots (DBS) � Polymerase chain reaction (PCR) � Pooling strategy � HIV screening
Introduction
Whole blood dried onto filter paper constitutes a potentially
useful material for molecular testing of viruses, including
HIV [1–3]. Though HIV is a RNA virus, once inside the
host CD4 cell following infection, HIV RNA is converted
to DNA. This viral DNA, after combining with host DNA,
exists as Proviral DNA. Dried blood spots (DBS) represent
a valuable and comprehensive genetic repository because
genomic DNA can be isolated from blood samples pro-
cessed on these filter papers for use in polymerase chain
reaction (PCR) [4]. Besides the extraction of DNA from
DBS, amplification from punches of DBS directly taken
into the PCR reaction mixture has been reported [5].
In spite of continuous improvements of the serological
assays, a residual risk that is extremely small still exists
attributed largely during the antibody-negative, pre sero-
conversion window period, the period between infection
and detectable seroconversion [1, 6]. Direct detection of
the virus can be achieved by nucleic acid test (NAT),
which enables detection of the viral nucleic acid. Previous
studies reported the detection of HIV DNA approximately
V. Lakshmi (&) � T. Sudha Nizam’s Institute of Medical Sciences, Hyderabad, AP, India
e-mail: vemulakshmigorthi@gmail.com
T. Sudha
e-mail: s_talasila@hotmail.com
D. Rakhi � G. Anilkumar � L. Dandona Public Health Foundation of India, New Delhi, India
e-mail: rakhi.dandona@phfi.org
L. Dandona
e-mail: lalit.dandona@phfi.org
L. Dandona
Institute for Health Metrics and Evaluation, University of
Washington, Seattle, Washington, USA
123
Indian J Microbiol (Apr–June 2011) 51(2):147–152
DOI 10.1007/s12088-011-0135-0
1 week earlier than detection of p24 antigen and about
2 weeks earlier than antibody detection [6, 7].
PCR technique was introduced in 1983 and the use of
DBS for PCR testing was first shown to have utility in 1987
[2] using in-house technique. Later, DBS PCR was adapted
to a standardized, commercially available microwell plate
amplification and detection kit, Amplicor HIV-1 produced
by Roche molecular systems [8]. Though several studies
have extracted DNA and RNA from a single DBS and
performed PCR for HIV DNA, there have been no reports
of performing HIV PCR on DBS that have been pooled
together. The principle of pooling is simply to mix a pre-
determined number of samples in a pool and test the pool
as one sample. Since pooling is a cost effective and time
saving way of performing nucleic acid tests, PCR on
pooled DBS is especially suited for samples that require
testing on large scale (e.g. samples from general
population).
With the absence of availability of any publications on
HIV PCR on pooled DBS, there has been a need of stan-
dardization and evaluation of the feasibility of performing
PCR for HIV-1 DNA from pooled DBS. The present study
was undertaken with an aim to evaluate the feasibility of
performing PCR for HIV-1 DNA on pools of DBS as an
alternative to individual testing.
Materials and Methods
Standardization of HIV-1 DNA PCR on Pooled DBS
DBS from five confirmed HIV reactives with known HIV-1
viral load (ranging between 500 and 600 copies/ml) in the
corresponding plasma sample and 32 HIV ELISA non-
reactive samples were used for standardization. All the five
HIV reactive DBS were positive for HIV-1 DNA when
tested individually to confirm that DNA could be detected
from DBS. Earlier reports have shown a good correlation
of HIV-1 viral load (quantitative test) in paired DBS and
plasma samples [3, 9]. Initially, the HIV status was deter-
mined on DBS collected from all these individuals using a
4th generation HIV ELISA [10].
Three groups of pools with 5, 10 and 20 DBS in each
were prepared as shown in Table 1. In each pool only one
known HIV reactive sample was included whereas the rest
of the DBS were from confirmed HIV non-reactive sam-
ples. Thus using five confirmed HIV reactive DBS a total
of 15 pools were prepared that included five pools of 5
DBS in each pool, five pools of 10 DBS in each pool and
five pools of 15 DBS in each pool. Viral load assay was
performed with Roche Amplicor version 1.5 monitor assay,
Roche molecular diagnostics, Branchburg, USA. For
obtaining DNA from DBS, a 6 mm punch was taken by
following the protocol as mentioned in several other
studies [8, 11, 12].
Preparation of DNA Pools from 5 DBS
For the 5 DBS pooling process, only one confirmed HIV-1
positive DBS sample with known viral load copies (S1)
was taken along with rest four confirmed HIV negative
samples (S2, S3, S4, S5). A 6 mm punch from each DBS
was extracted separately with 200 ll chelex reagent pro- vided in the Amplicor HIV-1 DNA test, version 1.5 by
following all the steps for extraction as mentioned in kit
insert [13]. After extracting all the 5 DBS separately, 10 ll from each extracted DNA sample was pooled together into
one PCR amplification tube, thus making the final volume
as 50 ll. This pooled extract was further processed by a qualitative PCR.
Preparation of DNA Pools from 10 DBS
For the 10 DBS pooling process, only one confirmed HIV
positive DBS sample with known viral load copies (S1)
was taken along with rest nine confirmed HIV negative
samples (S2, S3, S4, S5, S6, S7, S8, S9, S10). Instead of a
single DBS, two 6 mm punches, each taken from 2 sepa-
rate samples were extracted with 200 ll chelex reagent provided in the Amplicor HIV-1 DNA test, version 1.5 by
following all the steps for extraction as mentioned in kit
insert [13]. Thus five smaller pools of 2 DBS each were
prepared for extraction. After extracting all the five pools
of 2 DBS each, 10 ll from each was pooled together into one PCR amplification tube, thus making the final volume
Table 1 Pooling procedure for qualitative DNA PCR
standardisation
Number of DBS
pooled together
in each pool
Number of pools
prepared with
each positive DBS
DBS extracted
in 200 ll chelex using 6 mm punch
Amount of
DNA taken in
each test pool (ll)
5 5 1 10
10 5 2 10
20 5 2 5
148 Indian J Microbiol (Apr–June 2011) 51(2):147–152
123
as 50 ll. This pooled extract was further processed by a qualitative PCR.
Preparation of DNA Pool from 20 DBS
For the 20 DBS pooling process, only one confirmed positive
DBS sample with known viral load copies (S1) was taken
long with rest 19 confirmed HIV negative samples (S2–S20).
Instead of a single punch, two 6 mm punches, each taken
from two separate DBS were extracted with 200 ll chelex reagent provided in the Amplicor HIV-1 DNA test, version
1.5 by following all the steps for extraction as mentioned in
kit insert [13]. Thus ten smaller pools of 2 DBS each were
prepared for extraction. After extracting all the ten pools of 2
DBS each, 5 ll from each was pooled together into one PCR amplification tube, thus making the final volume as 50 ll. This pooled extract was further processed by a qualitative
PCR. Table 1 presents the detailed pooling procedures.
HIV-1 DNA PCR on Pooled DBS from Known HIV-1
Negative Individuals
Dried blood spots (DBS) were collected as part of population-
based HIV study of 12,617 respondents (aged 15–49 years)
from south India [14] where a blood sample by the finger-prick
method was obtained from these respondents on filter paper
(Whatman No. 3; Whatman International Ltd, Maidstone,
Kent, UK), preferably six drops of blood, without any anti-
coagulant on it. These blood drops were allowed to dry and
were stored in sealed polythene bags with desiccant in the field
office at room temperature and within 1 week were trans-
ported to the testing laboratory. In the laboratory, DBS were
stored under refrigeration at 2–8�C until testing for HIV-1 DNA was performed, maximum being within 1 year of col-
lection. Of these 12,617 respondents tested for HIV infection,
240 were found to be HIV positive. Of the samples negative
for both antibody and antigen, a subset of 585 samples
belonging to people who were considered at relatively high
risk of HIV and another set of 10% of all samples (1238)
negative for HIV antibody or antigen underwent qualitative
PCR (Amplicor 1.5; Roche molecular diagnostics, Branch-
burg, USA) testing for HIV viral nucleic acid to detect very
recent infections. After the successful standardisation of
pooled PCR, DBS from these 1,823 individuals who were
negative for both HIV antigen and antibodies were tested for
HIV-1 DNA by PCR by the optimized pooling procedure
(i.e. using 10 DBS pooling strategy).
DNA from 10 DBS each was pooled together, except for
a single pool that had only 3 DBS pooled together as
described above. To identify the positive DBS from the
positive pool, the DNA extracted from all the ten indi-
vidual DBS that were included in the positive pool were
processed again by HIV-1 PCR.
PCR Procedure
PCR for detecting the presence of HIV-1 proviral DNA in
all the above cases was performed by using Amplicor HIV-
1 DNA version 1.5 (Roche molecular diagnostics,
Branchburg, USA). The Amlicor HIV-1 DNA test, version
1.5 is based on four major processes: sample preparation;
PCR amplification of target DNA using HIV-1 specific
complementary primers; hybridization of the amplified
products to oligonucleotide probes specific to the target;
and detection of the probe-bound amplified products by
colorimetric determination [13].
Primers
Primers SK145 and SKCC1B supplied in the commercial kit
of Amlicor HIV-1 DNA test, version 1.5 are used to amplify a
155-nucleotide sequence of the HIV-1 gag gene [13].
RT and downstream PCR primer SKCC1B complemen-
tary to nucleotides 1485–1512 of HIV-1HXB2 is (5 0-TAC
TAGTAGTTCCTGCTATGTCACTTCC-30) and upstream primer SK145 (50-AGTGGGGGGACATCAAGCAGCCAT GCAAAT-30).
Preparation of Samples from DBS [2, 13]
A 6 mm punch of DBS was taken into a 1.5 ml screw-cap
tube containing 1.0 ml of blood wash solution (BLD WS)
and was incubated for 30 min at room temperature. After
micro-centrifugation for 3 min at maximum speed, super-
natant was aspirated; 1.0 ml of BLD WS was added to each
tube, recapped and vortexed. Tubes were microcentrifuged
for 3 min at maximum speed. All this was repeated again.
Supernatant was aspirated, being careful to avoid disturb-
ing the DBS. The dry DBS was extracted immediately
(alternatively it can be stored at -70�C until extraction). 200 ll working Extraction Reagent was added to each DBS and vortexed. Tubes were incubated for 30 min at 60�C ± 2�C in a dry heat block containing sand and then for 30 min at 100�C ± 2�C in a dry heat block containing sand. Samples were vortexed briefly and microcentrifuged for 3 s. 50 ll of samples was added to appropriate PCR reaction tubes con-
taining the working master mix. Rest of the steps for PCR test
was performed as mentioned in the kit insert [13].
Results
Standardization of HIV-1 DNA PCR on Pooled DBS
All the negative and positive controls in the HIV-1 DNA
PCR runs were valid. Results of all the 15 DNA pools from
the DBS are presented in Fig. 1 and Table 2. Internal
Indian J Microbiol (Apr–June 2011) 51(2):147–152 149
123
control (IC) that serves as an extraction and amplification
control was observed to have sufficiently high OD values
for all 15 pools, indicating that the control DNA in all the
pools was properly amplified.
Specificity, sensitivity, positive and negative predictive
values of the assay were all observed to be 100% when
tested on pools of 5 and 10 DBS as all the pools of 5 and 10
DBS pooled together were positive for HIV-1 PCR. It was
noted that DNA could be detected from only 2/5 pools
from the 20 DBS pooled together thus indicating a sensi-
tivity of only 60% and a negative predictive value of 98%
though both specificity and positive predictive values
remained to be 100%. Thus pooling of 20 DBS that indi-
cated 98.06% overall accuracy of the assay was ruled out.
Standardization of pooling procedure accordingly indicated
that pooling of 10 DBS gave an optimum result due to its
cost effectiveness compared to 5 DBS pooled together and
hence was then adopted for pooling the study samples.
HIV-1 DNA PCR on Pooled DBS from Known HIV-1
Negative Individuals
Only one pool from the 183 pools was positive by PCR.
From the single PCR positive study DBS pool, after per-
forming PCR on ten individual samples, 1 DBS was found
to be positive for HIV-1 DNA PCR. The results of PCR on
pooled DBS are presented in Fig. 2. By including this one
HIV-1 positive sample that was detected by PCR, total HIV
positive samples increased from 240 to 241. This single
positive sample was 0.4% of the total 241 HIV positive
cases from this population-based study. Pooling strategy
also resulted in 88% reduction in overall cost compared to
PCR testing on individual sample. It also resulted in a
considerable reduction in testing time; ten times less than
individual testing.
Discussion
In spite of a person screened as negative by a 4th genera-
tion HIV assay, only direct monitoring by sensitive NAT
would provide accurate data of HIV infection in the pop-
ulation being tested. However, NAT is too expensive and
labor-intensive for routine screening of single specimens.
Because of the high cost of PCR on individual samples,
costs saving strategies have been devised for large numbers
of samples. One such strategy is to mix a predetermined
number of the samples to be assayed to make a testing pool
and process this pool as one sample. A positive result will
3.21
2.38
2.912.8
2.16
0.13
2.13
0.16
1.89
0.11
3.27 3.133.24 3.02
2.56
NC =0.2
PC =0.8
0
0.5
1
1.5
2
2.5
3
3.5
0 1 2 3 4 5 6
Pools of DBS
O D
o f P
C R
5 DBS POOL 10 DBS POOL 20 DBS POOL NC PC NC
Fig. 1 Individual results of DBS pooled together for standardization [Arrowheads indicate the pools (20 DBS pooled together) that were reported as negative in spite of a positive sample among each of them]
Table 2 Standardization results of HIV-1 DNA PCR on pooled DBS
No. of DBS
pooled together
Range of PCR OD
for HIV-1 DNA
Range of OD
for Internal Control
No. of pools
tested
No. of positive
pools
No. of negative
pools
5 DBS 2.38–3.0 2.35–3.0 5 5 0
10 DBS 2.16–3.0 2.45–3.0 5 5 0
20 DBS 0.16–2.13 2.48–3.0 5 2 3
4th gen Elisa for HIV Ag/ab on DBS collected from a South Indian Study (N=12,617)
HIV-1 DNA PCR on total 183 pools (One pool had 3
DBS) (N = 1813)
Pools were prepared by taking 10 DBS in each pool (59 pools) last pool included 5
samples from subset -2 (N=580)
Positive pools = 1 pool (N= 10)
Negative pools = 124 pools (N=1233)
HIV-1 DNA PCR on individual 10 DBS from the positive pool
Positive pool was opened up into 10 DBS
Negative DBS (N=9) Positive DBS (N= 1) Total Negative DBS
(N=1,813)
Subset 1: DBS belonging to people at relatively high risk of
HIV (N=585)
Subset 2: 10% of all samples negative for HIV antibody or
antigen (N=1238)
HIV Positive (N=240)
Pools were prepared by taking 10 DBS in each pool (124 pools) (last pool had
3 DBS) (N=1233)
Negative pools = 58 pools (N=580)
Fig. 2 Results of HIV-1 DNA PCR on pooled DBS detected as negative for HIV antibody and antigen
150 Indian J Microbiol (Apr–June 2011) 51(2):147–152
123
indicate the presence of the viral DNA in one or more
samples within the pool and will necessitate retesting of
each of the samples that constituted the pool, so as to
identify the truly positive sample(s). On the other hand, a
negative result would indicate that none of the samples in
the pool contain the viral DNA.
The issue of sensitivity of PCR on pooled samples pri-
marily depends on dilution of the viral DNA. Hence, the
number of samples in the pool (pool size) has to be
optimized. In our study, the optimum pool size was
determined by using varying pool sizes, each containing
one known HIV-1 positive sample. The viral DNA could
be detected in all the pools with 5 and 10 DBS. However,
the 3/5 pools with 20 DBS were recorded false negative,
due to the dilution of the DNA below undetectable levels.
Since pooling of 10 DBS was more cost effective com-
pared to pools of 5 DBS, it was considered as the optimum
pool size and hence was used in our study.
Adopting the pooling strategy on 1,823 DBS from our
study samples resulted in detection of an additional one
positive sample by HIV-1 DNA PCR, making the total
number of HIV positive DBS to 241 out of 12,617 total
study samples. This PCR positive sample was actually
from the subset of 585 samples belonging to people who
were considered at relatively high risk of HIV and probably
was from an individual who was either in the early sero-
conversion phase of HIV infection or was on anti retroviral
therapy, the details of which were not available. Due to
insufficient sample, a quantitative PCR could not be per-
formed that would have indicated the viral load of the
positive sample and the probable time since sero-conver-
sion. Another set of 10% of all samples (1238) negative for
HIV antibody or antigen that underwent qualitative PCR in
pools of ten samples remained negative for HIV-1 DNA.
Pooling strategy also resulted in a considerable reduction
in overall cost and testing time compared to PCR testing on
individual testing. In spite of several advantages of PCR, one
limitation of the PCR test is that though theoretically 100%
sensitivity and specificity can be achieved, the observed
sensitivity of HIV-1 DNA PCR assays in clinical practice is
reported to be 96–99% [15–17] due to the undetectable levels
of viral DNA in the eclipse phase of infection i.e. 3–7 days
from exposure and infection [6].
Pooling strategy can be more cost effective for testing
HIV prevalence in research studies conducted on special-
ized population where the prevalence rates are low. How-
ever, such pooling strategy for PCR if applied to screen
high risk populations, the number of HIV case detections
can be increased cost effectively, only if all samples that
are negative for HIV Ag or Ab are pooled together, similar
to the strategy adapted in our study. But if all samples from
high risk population studies are pooled together, as an
initial step, then the pooling strategy may lose its cost
effectiveness as due to high prevalence of HIV infection,
quite a lot of of the pools will be positive and all samples in
the positive pool will need individual testing for detection
of HIV-1 DNA in the sample that may lead to higher cost
and also will be more time consuming.
Our study has demonstrated that PCR for HIV-1 DNA
can be successfully performed on pools of DBS with time
and cost savings without compromising the sensitivity of
the PCR.
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