Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure

Abstract

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.

Figure 1

Serial plasma RNA determinations in three subjects with history of therapy interruptions. Values are presented as log₁₀ copies of HIV RNA per ml by vertical bars, with the lowest values shown being the threshold of detection of the Amplicor assay. Periods of treatment interruptions are shown in shaded horizontal bars with the letter corresponding to the subject followed by the number of days of treatment interruption. Arrows indicate time of LN biopsy for each patient.

Figure 2

Correlation of HIV RNA levels in plasma and LN after 1 year of therapy. Values are represented as log₁₀ copies of HIV RNA for each subject. Plasma was obtained on the same day as the LN biopsy. Densely hatched bars, plasma HIV RNA (log₁₀ copies per ml); black bars, HIV RNA in LN (log₁₀ copies/4 × 10⁶ copies of TCR Cα mRNA); sparsely hatched bars, HIV RNA in LN (log₁₀ copies per mg). Values shown for LN are mean of two assays on different tissue fragments.

Figure 3

Correlation of HIV RNA levels in plasma and HIV DNA copy numbers in PBMC and lymph node after one year of therapy. Values for HIV RNA in plasma are log₁₀ copies per ml of plasma shown by densely hatched bars (right-hand axis). Values for HIV DNA are in copy numbers per 100 ng of cellular DNA or 16,000 cell equivalents (left-hand axis) shown as black bars for PBMC and sparsely hatched bars for LN. PBMC were obtained on the same day as the LN biopsy. HIV DNA copy numbers represent the mean of duplicate assays performed on the same DNA extract. No LN DNA extract was available for subject D. HIV DNA copy number in PBMC from subject B was approximately 1 in 64,000 cells. Quantitation from LN of patient J was omitted.