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      #44470 - 11/21/02 06:29 PM

Validation: Search for the Gold Standard

HIV tests should be validated against direct isolation of the virus from people that test positive, and lack of isolation in people who test negative.
Instead of just comparing people with AIDS against healthy people, tests should also be validated on people with non-AIDS diseases that may
cross-react (such as leprosy or malaria) and with other conditions that may generate a higher load than normal of antibodies (e.g. recent vaccination,
pregnancy, auto-immune disease). Isolation should be validated by purification of HIV particles, followed by microscope verification of purity, and
then by analysis of the constituent proteins and genetic material. This suite of tests is sometimes referred to as a 'Gold Standard' and has never been
performed for HIV, not even once.

“Primary infection was defined as a confirmed positive virologic test result with either a negative HIV antibody assay result or an indeterminate Western blot. Because
there is no virologic gold standard, we assumed that levels of plasma HIV RNA had a sensitivity of 100% for diagnosing primary infection [bonus marks for detecting
the flaw in this logic].False-positive HIV RNA measurements were defined as those that were negative on repeated testing and those obtained in patients who did not
undergo seroconversion [note the contradiction with the previous sentence]...Eight of 303 uninfected patients (2.6%) had false-positive results on HIV RNA testing”

Daar ES et al. Diagnosis of primary HIV-1 infection. Ann Int Med. 2001 Jan 2;134(1).

“At present there is no recognized standard for establishing the presence and absence of HIV-1 antibody in human blood.”

Human Immunodeficiency Virus Type 1 HIVAB HIV-1 EIA. Abbott Laboratories. 1997 Jan.

“The evaluation of the sensitivity and specificity of PCR for the diagnosis of HIV infection in infants is particularly difficult because there is no reference or ‘gold
standard’ test that determines unequivocally the true infection status of the patient [but antibody tests, generally agreed to be inapplicable to infants, hardly qualify as a
‘gold standard’, so the same problem occurs with all people being tested for HIV]...a single positive PCR test result does not provide definitive evidence of HIV
infection in infants...This finding holds even for more recent studies published after PCR technology had matured”

Owens DK et al. A Meta-analytic Evaluation of the Polymerase Chain Reaction for the Diagnosis of HIV Infection in Infants. JAMA. 1996 May

“This study assumed that the investigated samples were from non-HIV infected individuals. While we were unable to unequivocally prove this, samples were obtained
from normal blood donors who signed a declaration form stating that they had not engaged in any HIV-related risk behaviour. Because these individuals were healthy
enough to present for blood donation, it is unlikely that their indeterminant WB reactivities could have resulted from the loss of anti-core antibodies, which has been
associated with late-stage AIDS...the use of WB interpretive criteria, such as those proposed by the World Health Organization [would] allow individuals reactive to
two glycoprotein bands to be considered anti-HIV-1-seropositive, and would inappropriately classify 11 out of the 13 samples described in this study as
anti-HIV-1-seropositive by the DB [Diagnostic Biotechnology] WB”

Healey DS, Bolton WV. Apparent HIV-1 glyco-protein reactivity on Western Blot in uninfected blood donors. AIDS. 1993;7:655-8.

“Alloimmune mice...were shown to make antibodies against gp120 and p24 of human immunodeficiency virus (HIV), and mice of [two] autoimmune strains...made
antibodies against gp120. This is surprising because the mice were not exposed to HIV. [i.e. HIV proteins are found in uninfected mice!!]”

Kion TA, Hoffmann GW. Anti-HIV and anti-anti-MHC antibodies in alloimmune and autoimmune mice. Science. 1991 Sep 6;253:1138-40.

“Serologic assays identify persons with prior exposure to human immunodeficiency virus (HIV-1), they do not specifically determine current infection...The number
of peripheral blood lymphocytes expressing viral RNA, as detected by in situ hybridization in an infected person is less than 1 in 10,000 cells...Defective provirus
would be detected by the PCR technique provided the region targeted for amplification was preserved [i.e. antibody tests do not prove current infection, and viral
load/PCR tests cannot distinguish between defective and infectious HIV!]”

Ou CY et al. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science. 1988 Jan 15;239(4837):295-7.

“for HIV infection, there is no independent, unequivocal way of identifying a group of individuals who are all assuredly infected or uninfected”

Cleary PD et al. Compulsory premarital screening for the human immunodeficiency virus: Technical and public health considerations. JAMA.

“The meaning of positive tests will depend on the joint [ELISA/WB] false positive rate. Because we lack a gold standard, we do not know what that rate is now. We
cannot know what it will be in a large-scale screening program”

Meyer KB, Pauker SG. Screening for HIV: can we afford the false positive rate?. NEJM. 1987;317(4):238-41.

“Evaluation of a new test requires an established or known standard for comparison. At this point, however, no established standard exists for identifying HTLV-III
[HIV] infection in asymptomatic people. Current culture methods for [HIV] identify virus in only 36% to 85% of persons with AIDS or related conditions and cannot
be used as an absolute standard for HTLV-III/LAV [HIV] infection. For this reason, we defined [note: not ‘proved’] specimens positive on Western blot or culture as
positive for infection with [HIV]”

Ward JW et al. Laboratory and epidemiologic evaluation of an enzyme immunoassay for antivodies to HTLV-III. JAMA. 1986 Jul 18;256(3):357-61.

“We evaluated the validity of the test by determining whether the test could distinguish known patients with AIDS from the normal population and from groups that
might pose cross-reactivity problems [but not against actual detection of a virus]...Since the ELISA [antibody test] ratio [indicating the intensity of the antibody
reaction] was less than 5.0 in approximately 99% of these controls, serum samples with ratios of 5.0 or greater were defined as positive for HTLV-III [HIV]

Weiss SH et al. Screening test for HTLV-III (AIDS agent) antibodies: specificity, sensitivity, and applications. JAMA. 1985;253(2):221-5.

“in the interpretation of the results it is assumed that these 11 [HIV-negative samples from people in high risk groups] and all the BD [blood donor] and PFP
[potentially false-positive] specimens were negative and that the remaining 72 HRG [high risk group] specimens were the only true positive ones”

Mortimer PP et al. Which anti-HTLV-III/LAV assays for screening and confirmatory testing?. Lancet. 1985;2:873-7.

Viral Load (PCR; Polymerase Chain Reaction)

Viral load tests are often claimed to detect the genetic material of HIV, either the DNA embedded in infected cells or the RNA in viral particles
circulating in the body. Yet these tests search for only a small fraction of the HIV genome, and HIV has never been properly isolated to allow the
genome to be unambiguosly determined. Furthermore, the viral load test cannot distinguish between infectious and defective virus, and in some studies
only 1 out of 60,000 viral particles was estimated to be infectious (see section on discordance).

“We report in this work that HIV-1 and HIV-2 patients having a similar degree of CD4 depletion displayed similar levels of T cell hyperactivation and similar numbers
of cycling cells in the peripheral blood despite great differences in the plasma viral load. These results and other recent reports call for reevaluation of different
hypotheses about causal relationships among virus concentration, CD4 depletion, and activation and turnover of T lymphocytes.”

Sousa AE et al. CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load.
J Immunol. 2002 Sep 15;169:3400-6.

“The 2 articles recently published in JAMA are probably among the most important HIV-related papers of the year and have tremendous implications for
decision-making. They question the rather arbitrary viral load threshold used in current antiretroviral guidelines and suggest that the main factor that should influence
when to start therapy -- and maybe the only one to consider -- should be the CD4+ cell count. The only contributions that viral load can make to this decision are (a) to
determine how quickly a given individual is likely to reach the CD4+ cell count threshold at which therapy is indicated, and (b) perhaps to determine the frequency of
CD4+ cell-count monitoring. Monitoring viral load only becomes critical when therapy is started.”

Tebas P. When should antiretroviral therapy be initiated?. Medscape HIV/AIDS. 2002;8(1).

“The three tests for HIV-1 RNA were 100% sensitive for preseroconversion PHI [i.e. no people diagnosed with Primary HIV Infection symptoms by other methods
did not have detectable RNA]. However, bDNA [branched DNA] testing for PHI had a 5% false-positive rate, PCR testing had a 3% false-positive rate and the
transcription-mediated amplification assay had a 2% false-positive rate. The false-positive results on the bDNA test ranged from 584 to 2058 copies/ml. False-positive
PCR tests ranged from 58 to 103 copies/ml.”

Hecht FM et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS. 2002 May 24;16(8):1119-29.

“Several potential mechanisms could explain the transient suppression of HIV replication early during the course of measles. Measles virus infection results in
lymphopenia, with reductions in CD4+ T lymphocyte percentage and number. The nadir of the lymphopenia precedes the onset of rash, and values usually return to
normal by 1 month after the onset of the rash. This early reduction in CD4+ T lymphocytes could decrease the number of target cells for HIV replication. An
alternative explanation is that measles virus infection stimulates the production of soluble factor(s) capable of suppressing HIV replication.”

Moss WJ et al. Suppression of Human Immunodeficiency Virus Replication during Acute Measles. JID. 2002 Mar 25;184.

“The effect of highly active antiretroviral therapy (HAART) in 85 children infected with human immunodeficiency virus type 1 (HIV-1) was compared retrospectively
among Centers for Disease Control and Prevention (CDC) immunologic groups 1-3...HAART resulted in the suppression of HIV-1 below detectable levels in 34.8%,
25%, and 32% of patients in the 3 CDC groups, respectively, and in a frequent switch from syncytium-inducing to nonsyncytium-inducing virus. The results
support...the use of other markers of disease progression, in addition to virus load.

Nikolic-Djokic D et al. Immunoreconstitution in Children Receiving Highly Active Antiretroviral Therapy Depends on the CD4 Cell Percentage at Baseline.
JID. 2002 Feb 1;185:290-8.

“[Table 2 shows that the results for identical material sent to multiple laboratories provided viral load results varying from 3,849 to 1,291,635 (Roche Amplicor HIV-1
Monitor), from 63,750 to 205,500 (Bayer HIV-1 3.0 RNA) and from 89,000 to 360,000 (Organon Teknika NucliSens)]”

Guidelines for Laboratory Test Result Reporting of Human Immunodeficiency Virus Type 1 Ribonucleic Acid Determination. MMWR. 2001 Nov

“Autopsy samples from 13 HIV-infected subjects were examined for HIV-1 viral RNA (vRNA), and viral reverse transcriptase (RT) genotype was determined...The
median HIV-1 vRNA level in brain samples from [2] subjects with moderate dementia was 7.79 log(10) copies/g...compared with 5.44 log(10) copies/g for [3] mildly
demented subjects and 4.87 log(10) copies/g for those obtained from [7] nondemented individuals...[but] some demented subjects had relatively low levels of HIV-1
vRNA, and paradoxically some nondemented subjects had high vRNA brain levels”

McClernon DR et al. HIV in the brain: RNA levels and patterns of zidovudine resistance. Neurology. 2001 Oct 23;57:1396-1401.

“That a clinical benefit may not have been achieved with multi-drug rescue therapy calls into question the current wisdom of deeming an undetectable viral load the goal
of therrapy in the heavily pre-treated population. Even if it can be accepted that an undetectable viral load is an appropriate surrogate marker for clinically relevant
outcomes in treatment-inexperienced patients who are initiating combination therapy, it cannot necessarily be accepted without proof that it is a useful surrogate in
heavily pre-treated patients...Therefore, until controlled trials are able to prove the utility of an undetectable viral load as a surrogate marker for clinically relevant
outcomes in heavily pre-treated patients, we bleieve that clinicians should show caution before striving for complete viral suppression at any cost”

Deeks SG, Martin JN. Editorial Comment: Reassessing the goal of antiretroviral therapy in the heavily pre-treated HIV-infected patient. AIDS.

“The difference in HIV RNA between children on ZDV [AZT] and placebo was relatively small. After two years of ZDV, the proportion of IMM children [assigned to
AZT at the beginning of the trial, rather than deferred until AIDS developed] with high level (>50%) resistance to ZDV was quite low (38%), and 13% had no ZDV
associated mutations [meaning that viral resistance to therapy is not an explanation for anti-HIV therapy to reduce the amount of HIV in the body]”

Five year follow up of vertically HIV infected children in a randomised double blind controlled trial of immediate versus deferred zidovudine: the PENTA 1
trial. Arch Dis Child. 2001 Mar;84(3):230-6.

“Because of the RNA assay's 1.9% to 3.0% false-positive rate, results must be carefully interpreted and compared to HIV-1 viral load levels seen during proven HIV-1
seroconversion. We report the case of a sexually active woman with symptoms suggestive of ARS [Acute Retroviral Syndrome] who had a false-positive HIV-1 RNA
assay result”

More D et al. Utility of an HIV-1 RNA assay in the diagnosis of acute retroviral syndrome. S Med J. 2000 Oct;93(10):1004-6.

“Negative results (<50 copies/mL), were obtained in 30/32 (94%) [bDNA 3.0] assays [meaning that false-positive results were obtained in 2/32 or 6% of cases]”

Erice A et al. Performance characteristics of the bDNA 3.0 assy for quantitation of HIV-1 RNA in plasma [abstract]. 7th Conf. Retroviruses and Opp
Infections. 2000 Jan 30-Feb 2.

“In contrast to previous reports...the viral load in the majority of the [long-term survivors] tested was detectable and, in some [long-term survivors], quite high...and
variable over time.”

Betts MR et al et al. AIDS Res Hum Retro. 1999 Oct;15:1219-28.

“Participants with baseline RNA levels below the level defining virological response were excluded from the analysis [which creates an artificial downward trend in the
viral load, by eliminating people whose viral load might well go up on therapy]...In the ZDV-naive population [had not taken AZT before this trial] the maximum
median fall in HIV RNA occurred by 4 weeks for all three [treatment] arms [AZT, AZT+ddI, AZT+ddC]. Thereafter, the median HIV RNA increased towards baseline
levels [so you take these drugs for a lifetime for a theoretical benefit that lasts a month!]... The proportions responding (i.e. achieving HIV RNA [viral load] less than
800 copies/ml) in the first [year] in Delta 1 were 61% on ZDV-ddI and 45% on ZDV-ddC [and 10% on ZDV alone]. In Delta 2 [had previously taken AZT], the
proportion of responders [whose viral load dropped] was lower; 23% on ZDV-ddI, and 30% on ZDV-ddC [and 2% on ZDV alone]”

Delta Coordinating Committee et al. HIV-1 RNA response to antiretroviral treatment in 1280 participants in the Delta Trials: an extended virology study.
AIDS. 1999;13:57-65.

“The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number
(3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status.”

Hockett RD et al. Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA. J Exp Med.
1999 May 17;189(10):1545-54.

“Plasma viral load tests for HIV-1 were neither developed nor evaluated for the diagnosis of HIV-1 infection; therefore their diagnostic specificity is not well delineated
when applied to persons who are negative for HIV antibody. We report two cases of false-positive results obtained by using branched-chain DNA assay...and one using HIV reverse transcriptase polymerase chain reaction (RT-PCR)...These three cases illustrate the potential problems of using HIV-1 plasma viral load
tests for diagnosis of HIV infection...Only patients who have a high pre-test probability of a positive result should be evaluated for primary infection by using plasma
viral load testing [i.e. preconceptions about risk groups such as gay men makes a positive test more likely]...Their performance in patients who are not infected with
HIV is unknown”

Rich JD et al. Misdiagnosis of HIV Infection by HIV-1 Plasma Viral Load Testing: A Case Series. Ann Int Med. 1999 Jan 5;130(1):37-9.

“Peak levels [of HIV-1 RNA] in the first 120 days were not predictive of disease progression”

Schacker TW et al. Biological and Virologic Characteristics of Primary HIV Infection. Ann Int Med. 1998 Apr 15;128:613-20

“We observed that clade A strains [of HIV] were not detected by RT-PCR [Reverse Transcriptase-Polymerase Chain Reaction] and that clade G-strains were not
detected by NASBA [Nucleic Acid Sequence-Based Amplification]. However, the copy number detected by RT-PCR in one clade E (CM235) and in one clade F
(163.3070) was much lower than the copy number detected by bDNA [branched DNA] and NASBA...for clades B and D (UG270), the HIV-1 RNA levels measured
by bDNA were lower than those obtained by RT-PCR and NASBA”

Coste J et al. Effect of HIV-1 genetic diversity on HIV-1 RNA quantification in plasma: comparative evaluation of three commercial assays. JAIDS.

“[In this study of 78 HIV-positive people with high CD4 cell counts and no symptoms] there were no differences in viral load with regard to time of HIV-1 infection
[i.e. amount of virus does not grow over time]…10 patients fulfilled the criteria for LTNP [Long Term Non-Progressors]. 7 of these 10 patients had viral loads above
10,000 RNA copies/ml and 2 above 30,000 RNA copies/ml. The level of viral load of LTNP was not statistically different compared with the other 68 patients”

García F et al. Viral load in asymptomatic patients with CD4+ lymphocyte counts above 500 million/l. AIDS. 1997;11:53-7.

“Specimens were tested twice with PCR; only those for which PCR reaction was repeatedly positive were reported as positive [which indicates that false positives
occurred at a significant level, although no numbers were reported. Furthermore, if a false positive can occur once, it can occur twice]”

Bertolli J et al. Estimating the timing of mother-to-child transmission of human immunodeficiency virus in a breast-feeding population in Kinshasa, Zaire. JID.
1996 Oct;174:722-726.

“for 223 specimens for HIV-infected infants [based on two positive co-cultures], 89% had PCR positivity, 11% had PCR negativity and <1% had indeterminate

Bremer JM et al. Diagnosis of infection with human immunodeficiency virus type 1 by a DNA polymerase chain reaction assay among infants enrolled in the
women and infant's transmission study. J Pediatr. 1996 Aug;129(2):198-207.

“The AMPLICOR HIV-1 MONITOR Test is an in vitro nucleic acid amplification test for the quantitation of Human Immunodeficiency Virus Type 1 (HIV-1) RNA
in human plasma...[It] is not intended to be used as a screening test for HIV or as a diagnostic test to confirm the presence of HIV infection...Quantitative culture has
limited utility for monitoring virus levels in infected individuals since only a small fraction of virus particles is infectious in vitro. Infectious virus is often undetectable
in asymptomatic individuals...The clinical specificity of the...test was determined by analysis of 495 anti-HIV-1 negative blood donors. None of these specimens was
reactive...Assuming a zero prevalence of HIV-1 infection in the seronegative blood donors, the specificity of the test was 100%”

Amplicor HIV-1 Monitor Test. Roche. 1996.

“maintenance of plasma HIV RNA levels below 10,000/ml in early HIV disease appears to be associated with decreased risk of progression to AIDS. However, in
patients with more advanced disease [low CD4 cell counts], disease progression occurred in up to 30% of patients with fewer than 10,000 HIV RNA copies/ml [In
other words, viral load is not terribly well associated with progression to AIDS]...HIV RNA levels should not be measured within a month of acute illnesses or within a
month after influenza and pneumococcus immunizations. Increases in HIV RNA levels in blood of as much as 300-fold have been observed within two weeks of
routine immunizations against influenza, tetanus, or pneumococcus”

Saag MS et al. HIV viral load markers in clinical practice. Nat Med. 1996 Jun;2(6):625-9.

“"Our investigation produced two main findings. First, the false-positive and false-negative rates of PCR that we determined are too high to warrant a broader role for
PCR in either routine screening or in the confirmation of diagnosis of HIV infection. This conclusion is true even for the results reported from more recent,
high-quality studies that used commercially available, standardized PCR assays...We did not find evidence that the performance of PCR improved over time2”

Owens DK et al. Polymerase chain reaction for the diagnosis of HIV infection in adults. A meta-analysis with recommendations for clinical practice and study
design. Ann Int Med. 1996;124:803-15.

“the majority (83%) of [flu] vaccinated [HIV-positive] invidiuals experienced a significant increase in plasma HIV-1 RNA levels within 1-2 [weeks after] immunization
and returned to their prevaccination levels within 4 weeks after immunization...patients on antiretroviral therapy were not noticeably different from those not in therapy
with regard to increases in plasma viremia”

Staprans SI et al. Activation of virus replication after vaccination of HIV-1 infected individuals. J Exp Med. 1995 Dec 1;182(6):1727-37.

“the high level of plasma virus observed by Piatak et al, was about 99.9 per cent non-culturable, suggesting that it was either neutralized or defective.”

Sheppard HW, Ascher MS, Krowka JF. Viral burden and HIV disease. Nature. 1993 Jul 22;364(6435):291-2.

“96% (105 of 110) of all [HIV-positive] patients tested had quantifiable plasma RNA [although that is high, one wonders how the others can have HIV in their bodies
without detectable amounts of HIV RNA (free HIV particles) using PCR, an extraordinarily sensitive method]”

Winters MA et al. Biological variation and quality control of plasma Human Immunodeficiency Virus type 1 RNA quantitation by reverse transcriptase
Polymerase Chain Reaction. J Clin Microbiol. 1993;31(11):2960-6.

“Circulating levels of plasma virus determined by QC-PCR also correlated with, but exceeded by an average of nearly 60,000-fold..., titers [amounts] of infectious
HIV-1 determined by quantitative endpoint dilution culture of identical portions of plasma.”

Piatak M Jr et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993 Mar 19;259:1749-54.

“Our study of PBMC [Peripheral Blood Mononuclear Cells] from 56 HIV-1-seropositive patients, using in situ hybridization alone, also [as did other studies]
revealed only 1 in 5,000 to 1 in 100,000 cells positive for HIV-1-specific nucleic acids [DNA]...Our finding with the use of in situ PCR that large numbers [if you
consider 0.1% to 13.5% of cells a ‘large number’] of PBMC from HIV-1-seropositive patients contain the provirus suggests that direct cytopathic [cell-killing] effects
of the virus may be an important but not necessarily the sole cause of depletion of CD4-positive lymphocytes. Our data also argue strongly against the theory that
HIV-1 is not the primary etiologic [causative] agent of AIDS [huh?]...we were able a relation between viral load and the stage of HIV-1 clinical infection.
Patients in Stage II [HIV+, but no symptoms] had a significantly lower percentage of HIV-1-positive PBMC than those in Stage III and Stages IV-A to IV-C [but the
authors neglect to mention that this is only true of the average value, there was considerable overlap between individual values. More importantly, they also do not
mention that the average value at Stage III (lymph gland enlargement) was higher than at Stage IV-A to C (AIDS) and much higher than at Stage IV-D (Kaposi’s
Sarcoma)]. Patients in Stage IV-D (who had Kaposi’s sarcoma only) had relatively low numbers of HIV-1-infected cells.”

Bagasra O et al. Detection of human immunodeficiency virus type 1 provirus in mononuclear cells by in situ polymerase chain reaction. NEJM.

“This proficiency study of PCR detection of HIV-1 DNA in serum identified a disturbingly high rate of nonspecific positivity with a widely employed gag primer pair
system. In fact, the overall rate of positivity was not significantly different for serum specimens from seropositive patients and seronegative control donors (26% versus

Busch MP et al. Poor sensitivity, specificity, and reproducibility of detection of HIV-1 DNA in serum by polymerase chain reaction (PCR). JAIDS.

“PCR performed before the age of 1 month identified only 55% of the truly infected infants”

Van de Perre P et al. Postnatal transmission of Human Immunodeficiency Virus 1 from mother to infant: a prospective cohort study in Kigali, Rwanda. NEJM.

“The [HIV-1 DNA PCR, ‘viral load’] assay did not appear more sensitive than classic serologic tests in the diagnosis of HIV-1 infection [all seronegative individuals
were negative on DNA PCR, including those who had had unprotected sex with seropositive people] was even less sensitive, because the specimen from one of our
seropositive individuals was negative on PCR with the three primer pairs. Our results are consistent with...Jackson, Taylor, and Lifson...However, our results are not
consistent with those of other studies: Loche, Wolinski, Imagawa, and Ameisen observed positive PCRs in seronegative at-risk individuals. These discrepancies are
difficult to explain.”

Lefrere JJ et al. No evidence of frequent HIV-1 infection in seronegative at-risk individuals. Transfusion. 1991;31(3):205-11.

“We found that in infected but asymptomatic patients with HIV-1, [an average of] 1 in 50,000 PBMC harbored the virus. When such a patient’s condition progressed
to AIDS-related complex or AIDS, the viral titer increased significantly, to approximately 1 in 400 PBMC...It is unclear from this study, however, what percentage of
the infected cells carry HIV-1 latently and what percentage of the cells express the virus actively. If 1 in 10,000 viral messenger RNA...then 99.6% of
the infected monuclear cells harbor the virus latently and the remaining 0.4 % express it actively [i.e. 1 in 100,000 cells have active virus!]...this information on the
quantitation of HIV-1 [3high levels of HIV-1 viremia2] should reduce residual doubts about whether HIV-1 is the true etiologic agent of AIDS”

Ho DD et al. Quantitation of Human Immunodeficiency Virus type 1 in the blood of infected persons. NEJM. 1989;321(24):1621-5.

“we analyzed samples from individuals konwn to be at especially high risk of HIV infection-seronegative sexual partners of seropositive individuals...Of 16
seronegative partners tested, 5 were unequivocally positive for HIV DNA. The clinical records of these 5 subjects confirmed that they were seronegative by
enzyme-linked immunsorbent assay and western blot and negative for the p24 antigen at the time the blood samples were taken for the DNA assay...the same 5 samples
were found to be positive with a second HIV-specific oligonucleotide...The serological [antibody] status was confirmed in each case and each of the 5 individuals was
negative for anti-HIV antibodies and p24 antigen 2 and 3 months after the initial detection of HIV DNA”

Loche M, Mach B. Identification of HIV-infected seronegative individuals by a direct diagnostic based on hybridization to amplified viral DNA. Lancet.

“A reanalysis is presented of 43 cases of apparent transient viremina [one or more positive culture or PCR assays for HIV-1 and the subsequent inability to detect
HIV-1 in the speciments on multiple occasions or seroreversion, or both]. 41 cases occurred among 1561 infants in five studies of mother-to-infant HIV-1
transmission...Our negative studies of 43 cases of suspected transient infection indicate that the phenomenon...remains to be proven and that most cases suggestive of
transient HIV-1 infection are cases of mislabeling of specimens or their contamination in the laboratory...”

Frenkel LM et al. Genetic Evaluation of Suspected Cases of Transient HIV-1 Infection of Infants. Science. 15 May 1998;280:1073-1077.

“Specimens were studied from one mother and her child, both with suspected transient viremia. The mother had two and the infant three positive HIV-1 cultures, but
subsequently both individuals became negative for HIV-1 by nPCR, standard virus cultures, CD8+-depleted virus cultures, and enzyme-linked immunsorbent assay.
HIV-1 RNA and DNA were not detected in two lymph nodes taken from the mother 3 and 4 years after the last virus-positive culture. PCR amplification and DNA
sequencing of HIV-1 env sequences from the mother’s two and the child’s three culture supernatants were performed in separate laboratories to eliminate the
possibility of cross-contamination. Phylogenetic analysis found that none of the five isolates were genetically linked. Although it is improbable, these five virus isolates
appear to have arisen from five separate incidents of speciment contamination or mislabeling. This case remains enigmatic, however, in that both the mother and infant
had strong CD8+ cytotoxic T lymphocyte (CTL) responses and lymphocyte proliferation to multiple HIV-1 antigens”

Frenkel LM et al. Genetic Evaluation of Suspected Cases of Transient HIV-1 Infection of Infants. Science. 15 May 1998;280:1073-10

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